Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof

ABSTRACT

The present invention provides pyrazole derivatives represented by the general formula: 
                         
wherein R 1  represents H, an optionally substituted C 1-6  alkyl group etc.; one of Q and T represents a group represented by the general formula:
 
                         
or a group represented by the general formula:
 
                         
while the other represents an optionally substituted C 1-6  alkyl group etc.; R 2  represents H, a halogen atom, OH, an optionally substituted C 1-6  alkyl group etc.; X represents a single bond, O or S; Y represents a single bond, a C 1-6  alkylene group etc.; Z represents CO or SO 2 ; R 4  and R 5  represent H, an optionally substituted C 1-6  alkyl group etc.; and R 3 , R 6  and R 7  represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complications or obesity, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.

This application is a divisional of application Ser. No. 10/523,820,filed Feb. 4, 2005, now U.S. Pat. No. 7,375,087, which is a 371 ofPCT/JP2003/010048 filed Aug. 7, 2003, claiming the benefit of JapaneseApplication No. 232074/2002 filed Aug. 8, 2002 and Japanese ApplicationNo. 321729/2002 filed Nov. 5, 2002, all of which are hereby incorporatedby reference.

TECHNICAL FIELD

The present invention relates to pyrazole derivatives, pharmaceuticallyacceptable salts thereof or prodrugs thereof which are useful asmedicaments, pharmaceutical compositions comprising the same,pharmaceutical uses thereof and intermediates for production thereof.

More particularly, the present invention relates to pyrazole derivativeshaving an inhibitory activity in human SGLT1, pharmaceuticallyacceptable salts thereof or prodrugs thereof which are useful as agentsfor the prevention or treatment of a disease associated withhyperglycemia such as diabetes, impaired glucose tolerance, impairedfasting glycemia, diabetic complications or obesity, pharmaceuticalcompositions comprising the same, pharmaceutical uses thereof andintermediates for production thereof.

BACKGROUND ART

Diabetes is one of lifestyle-related diseases with the background ofchange of eating habit and lack of exercise. Hence, diet and exercisetherapies are performed in patients with diabetes. Furthermore, when itssufficient control and continuous performance are difficult, drugtreatment is simultaneously performed. In addition, it has beenconfirmed by large-scale clinical trial that it is necessary to practicea long-term control of blood sugar level strictly so as to preventpatients with diabetes from occurring and advancing diabeticcomplications by receiving treatment (see the following References 1 and2). Furthermore, many epidemiologic studies on impaired glucosetolerance and macroangiopathy show that impaired glucose tolerance asthe boundary type is also a risk factor in macroangiopathy as well asdiabetes. Thus, needs to improve postprandial hyperglycemia have beenfocused (see the following Reference 3).

In recent years, development of various antidiabetic agents has beenprogressing with the background of a rapid increase of patients withdiabetes. For example, α-glucosidase inhibitors, which delaycarbohydrate digestion and absorption at the small intestine, are usedto improve postprandial hyperglycemia. It has been also reported thatacarbose, one of α-glucosidase inhibitors, has an effect of preventingor delaying the incidence of diabetes by applying to patients withimpaired glucose tolerance (see the following Reference 4). However,since α-glucosidase inhibitors do not affect elevated glucose levels byingesting a monosaccharide of glucose (see the following Reference 5),with recently changing compositions of sugars in meals, it has beendesired to develop agents which exert a wider range of activitiesinhibiting carbohydrate absorption.

In the meantime, it has been known that SGLT1, sodium-dependent glucosetransporter 1, exists in the small intestine which controls carbohydrateabsorption. It has been also reported that insufficiency of glucose andgalactose absorption arises inpatients with dysfunction due tocongenital abnormalities of human SGLT1 (see the following References6-8). In addition, it has been confirmed that SGLT1 is involved inglucose and galactose absorption (see the following References 9 and10).

Furthermore, it is confirmed that mRNA and protein of SGLT1 increase andabsorption of glucoses are accelerated in OLETF rats and rats withstreptozotocin-induced diabetic symptoms (see the following References11 and 12). Generally in patients with diabetes, carbohydrate digestionand absorption are increased. For example, it is confirmed that mRNA andprotein of SGLT1 are highly increased in the human small intestine (seethe following Reference 13).

Therefore, blocking a human SGLT1 activity inhibits absorption ofcarbohydrates such as glucose at the small intestine, subsequently canprevent increase of blood sugar level. Especially, it is considered thatdelaying glucose absorption based on the above mentioned mechanism iseffective to normalize postprandial hyperglycemia. In addition, sinceincrease of SGLT1 in the small intestine is thought to contribute toincreased carbohydrate absorption, fast development of agents, whichhave a potent inhibitory activity in human SGLT1, has been desired forthe prevention or treatment of diabetes.

-   Reference 1: The Diabetes Control and Complications Trial Research    Group, N. Engl. J. Med., 1993.9, Vol. 329, No. 14, pp. 977-986;-   Reference 2: UK Prospective Diabetes Study Group, Lancet, 1998.9,    Vol. 352, No. 9131, pp. 837-853;-   Reference 3: Makoto, TOMINAGA, Endocrinology & Diabetology, 2001.11,    Vol. 13, No. 5, pp. 534-542;-   Reference 4: Jean-Louis Chiasson and 5 persons, Lancet, 2002.6, Vol.    359, No. 9323, pp. 2072-2077;-   Reference 5: Hiroyuki, ODAKA and 3 persons, Journal of Japanese    Society of Nutrition and Food Science, 1992, Vol. 45, No. 1, pp.    27-31;-   Reference 6: Tadao, BABA and 1 person, Supplementary volume of    Nippon Rinsho, Ryoikibetsu Shokogun, 1998, No. 19, pp. 552-554;-   Reference 7: Michihiro, KASAHARA and 2 persons, Saishin Igaku,    1996.1, Vol. 51, No. 1, pp. 84-90;-   Reference 8: Tomofusa, TSUCHIYA and 1 person, Nippon Rinsho, 1997.8,    Vol. 55, No. 8, pp. 2131-2139;-   Reference 9: Yoshikatsu, KANAI, Kidney and Dialysis, 1998.12, Vol.    45, extra edition, pp. 232-237;-   Reference 10: E. Turk and 4 persons, Nature, 1991.3, Vol. 350, pp.    354-356;-   Reference 11: Y. Fujita and 5 persons, Diabetologia, 1998, Vol. 41,    pp. 1459-1466;-   Reference 12: J. Dyer and 5 persons, Biochemical Society    Transactions, 1997, Vol. 25, p. 479S;-   Reference 13: J. Dyer and 4 persons, American Journal of Physiology,    2002.2, Vol. 282, No. 2, pp. G241-G248

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find compounds having aninhibitory activity in human SGLT1. As a result, it was found thatcertain pyrazole derivatives represented by the following generalformula (I) show an inhibitory activity in human SGLT1 at the smallintestine and exert an excellent inhibitory activity in increase ofblood glucose level as shown below, thereby forming the basis of thepresent invention.

The present invention is to provide novel pyrazole derivatives whichexert an excellent inhibitory activity of blood glucose level increaseby showing an inhibitory activity in human SGLT1 and inhibitingabsorption of carbohydrate such as glucose at the small intestine,pharmaceutically acceptable salts thereof or prodrugs thereof, and toprovide pharmaceutical compositions comprising the same, pharmaceuticaluses thereof and intermediates for production thereof.

This is, the present invention relates to

[1] a pyrazole derivative represented by the general formula:

wherein

R¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkyl group, a C₃₋₇cycloalkyl-substituted (C₁₋₆ alkyl) group, an aryl group which may havethe same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, or an aryl(C₁₋₆ alkyl) group whichmay have the same or different 1 to 3 substituents selected from thegroup consisting of a halogen atom, a hydroxy group, an amino group, aC₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring;

one of Q and T represents a group represented by the formula:

or a group represented by the formula:

while the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group,a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group;

R² represents a hydrogen atom, a halogen atom, a hydroxy group, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a halo(C₁₋₆alkyl) group, a halo(C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy-substituted (C₁₋₆alkoxy) group, a C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group or agroup of the general formula: -A-R⁸ in which A represents a single bond,an oxygen atom, a methylene group, an ethylene group, —OCH₂— or —CH₂O—;and R⁸ represents a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkylgroup, an aryl group which may have the same or different 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, an amino group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,a C₂₋₆ alkenyloxy group, a halo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl)group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, a cyano group and anitro group, or a heteroaryl group which may have a substituent selectedfrom the group consisting of a halogen atom and a C₁₋₆ alkyl group;

X represents a single bond, an oxygen atom or a sulfur atom;

Y represents a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylenegroup with the proviso that X is a single bond when Y is a single bond;

Z represents a carbonyl group or a sulfonyl group;

R⁴ and R⁵ are the same or different, and each represents a hydrogen atomor a C₁₋₆ alkyl group which may have the same or different 1 to 3 groupsselected from the following substituent group (i), or they bind togetherwith the neighboring nitrogen atom to form a C₂₋₆ cyclic amino groupwhich may have a substituent selected from the group consisting of aC₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group;

R³, R⁶ and R⁷ are the same or different, and each represents a hydrogenatom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group; and

substituent group (i) consists of a hydroxy group, an amino group, amono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆alkyl)]amino group, an ureido group, a sulfamide group, a mono ordi(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, aC₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a group of thegeneral formula: —CON(R⁹)R¹⁰ in which R⁹ and R¹⁰ are the same ordifferent, and each represents a hydrogen atom or a C₁₋₆ alkyl groupwhich may have the same or different 1 to 3 substituents selected fromthe group consisting of a hydroxy group, an amino group, a mono ordi(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group,an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylaminogroup, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or theybind together with the neighboring nitrogen atom to form a C₂₋₆ cyclicamino group which may have a substituent selected from the groupconsisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, a C₃₋₇cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which mayhave the same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have asubstituent selected from the group consisting of a halogen atom and aC₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituentselected from the group consisting of a C₁₋₆ alkyl group and ahydroxy(C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group whichmay have a C₁₋₆ alkyl group as a substituent,

or a pharmaceutically acceptable salt thereof;

[2] a pyrazole derivative described in the above [1] wherein Yrepresents a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group; one of R⁴and R⁵ represents a C₁₋₆ alkyl group which has the same or different 1to 3 groups selected from the following substituent group (i), the otherrepresents a hydrogen atom or a C₁₋₆ alkyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(i); and substituent group (i) consists of a hydroxy group, an aminogroup, a mono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆alkyl)]amino group, an ureido group, a sulfamide group, a mono ordi(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, aC₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a group of thegeneral formula:

—CON(R⁹)R¹⁰ in which R⁹ and R¹⁰ are the same or different, and eachrepresents a hydrogen atom or a C₁₋₆ alkyl group which may have the sameor different 1 to 3 substituents selected from the group consisting of ahydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, amono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono ordi(C₁₋₆ alkyl)-ureido group, a C₂₋₇ acylamino group, a C₁₋₆alkylsulfonylamino group and a carbamoyl group, or they bind togetherwith the neighboring nitrogen atom to form a C₂₋₆ cyclic amino groupwhich may have a substituent selected from the group consisting of aC₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, a C₃₋₇ cycloalkylgroup, a C₂₋₆ heterocycloalkyl group, an aryl group which may have thesame or different 1 to 3 substituents selected from the group consistingof a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituentselected from the group consisting of a halogen atom and a C₁₋₆ alkylgroup, a C₂₋₆ cyclic amino group which may have a substituent selectedfrom the group consisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆alkyl) group, and a C₁₋₄ aromatic cyclic amino group which may have aC₁₋₆ alkyl group as a substituent, or a pharmaceutically acceptable saltthereof;

[3] a pyrazole derivative described in the above [2] wherein one of R⁴and R⁵ represents a C₁₋₆ alkyl group which has a group selected from thefollowing substituent group (iA), the other represents a hydrogen atom;and substituent group (iA) is a group of the general formula:—CON(R^(9A))R^(10A) in which R^(9A) and R^(10A) bind together with theneighboring nitrogen atom to form a C₂₋₆ cyclic amino group which mayhave a substituent selected from the group consisting of a C₁₋₆ alkylgroup and a hydroxy(C₁₋₆ alkyl) group, or a pharmaceutically acceptablesalt thereof;

[4] a pyrazole derivative described in anyone of the above [1]-[3]wherein X represents a single bond; and Y represents a trimethylenegroup or a 1-propenylene group, or a pharmaceutically acceptable saltthereof;

[5] a pyrazole derivative described in anyone of the above [1]-[3]wherein X represents an oxygen atom; and Y represents an ethylene groupor a trimethylene group, or a pharmaceutically acceptable salt thereof;

[6] a pyrazole derivative described in the above [1] wherein Xrepresents a single bond; Y represents a single bond; one of R⁴ and R⁵represents a C₁₋₆ alkyl group which has the same or different 1 to 3groups selected from the following substituent group (iB), the otherrepresents a hydrogen atom or a C₁₋₆ alkyl group which may have the sameor different 1 to 3 groups selected from the following substituent group(iB); and substituent group (iB) consists of an ureido group, asulfamide group, a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆alkyl)sulfamide group, a C₁₋₆ alkylsulfonylamino group, a group of thegeneral formula: —CON(R^(9B))R^(10B) in which one of R^(9B) and R^(10B)represents a C₁₋₆ alkyl group which has the same or different 1 to 3substituents selected from the group consisting of a hydroxy group, anamino group, a mono or di(C₁₋₆ alkyl)amino group, a mono ordi[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or di(C₁₋₆alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylaminogroup and a carbamoyl group, the other represents a hydrogen atom, aC₁₋₆ alkyl group which may have the same or different 1 to 3substituents selected from the group consisting of a hydroxy group, anamino group, a mono or di(C₁₋₆ alkyl)amino group, a mono ordi[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or di(C₁₋₆alkyl)-ureido group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylaminogroup and a carbamoyl group, or they bind together with the neighboringnitrogen atom to form a C₂₋₆ cyclic amino group which may have asubstituent selected from the group consisting of a C₁₋₆ alkyl group anda hydroxy(C₁₋₆ alkyl) group, a C₃₋₇ cycloalkyl group, a C₂₋₆heterocycloalkyl group, an aryl group which may have the same ordifferent 1 to 3 substituents selected from the group consisting of ahalogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and aC₁₋₆ alkoxy group, a heteroaryl group which may have a substituentselected from the group consisting of a halogen atom and a C₁₋₆ alkylgroup, a C₂₋₆ cyclic amino group which may have a substituent selectedfrom the group consisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆alkyl) group, and a C₁₋₄ aromatic cyclic amino group which may have aC₁₋₆ alkyl group as a substituent, or a pharmaceutically acceptable saltthereof;

[7] a pyrazole derivative described in anyone of the above [1]-[6]wherein R¹ represents a hydrogen atom or a hydroxy(C₂₋₆ alkyl) group; Trepresents a group represented by the formula:

or a group represented by the formula:

Q represents a C₁₋₆ alkyl group or a halo(C₁₋₆ alkyl) group; and R³, R⁶and R⁷ represent a hydrogen atom, or a pharmaceutically acceptable saltthereof;

[8] a pyrazole derivative described in anyone of the above [1]-[6]wherein one of Q and T represents a group represented by the formula:

the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group, aC₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group,or a pharmaceutically acceptable salt thereof;

[9] a pyrazole derivative described in the above [7] or [8] wherein Trepresents a group represented by the formula:

or a pharmaceutically acceptable salt thereof;

[10] a pyrazole derivative described in the above [7] or [9] wherein Qrepresents an isopropyl group, or a pharmaceutically acceptable saltthereof;

[11] a prodrug of a pyrazole derivative described in any one of theabove [1]-[10] or a pharmaceutically acceptable salt thereof;

[12] a prodrug described in the above [11] wherein T represents a grouprepresented by the formula:

or a group represented by the formula:

in which the hydroxy group at the 4-position is substituted by aglucopyranosyl group or a galactopyranosyl group, or the hydroxy groupat the 6-position is substituted by a glucopyranosyl group, agalactopyranosyl group, a C₂₋₇ acyl group, a C₁₋₆ alkoxy-substituted(C₂₋₇ acyl) group, a C₂₋₇ alkoxy-carbonyl-substituted (C₂₋₇ acyl) group,a C₂₋₇ alkoxycarbonyl group, an aryl(C₂₋₇ alkoxycarbonyl) group or aC₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group;

[13] a pyrazole derivative described in the above [1] which is acompound selected from the following group:

-   4-[(4-{3-[1-carbamoyl-1-(methyl)ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamino)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole;-   4-[(4-{3-[1-(2-aminoethylcarbamoyl)-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-3-(β-D-galactopyranosyl-oxy)-5-isopropyl-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-isopropylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl-carbamoyl}propyl)phenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl-carbamoyl}propoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-1-(3-hydroxypropyl)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-galacto-pyranosyloxy)-5-isopropyl-1H-pyrazole;-   4-{[2-chloro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-glucopyranosyl-oxy)-5-isopropyl-1H-pyrazole,    and    pharmaceutically acceptable salts thereof;

[14] a pyrazole derivative described in the above [13] which is acompound selected from the following group:

-   3-(β-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole;-   4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-galacto-pyranosyloxy)-5-isopropyl-1H-pyrazole,    and    pharmaceutically acceptable salts thereof;

[15] a pharmaceutical composition comprising as an active ingredient apyrazole derivative described in any one of the above [1]-[14], apharmaceutically acceptable salt thereof or a prodrug thereof;

[16] a human SGLT1 inhibitor comprising as an active ingredient apyrazole derivative described in any one of the above [1]-[14], apharmaceutically acceptable salt thereof or a prodrug thereof;

[17] an agent for inhibiting postprandial hyperglycemia comprising as anactive ingredient a pyrazole derivative described in any one of theabove [1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof;

[18] an agent for the prevention or treatment of a disease associatedwith hyperglycemia, which comprises as an active ingredient a pyrazolederivative described in any one of the above [1]-[14], apharmaceutically acceptable salt thereof or a prodrug thereof;

[19] an agent for the prevention or treatment described in the above[18] wherein the disease associated with hyperglycemia is a diseaseselected from the group consisting of diabetes, impaired glucosetolerance, diabetic complications, obesity, hyperinsulinemia,hyperlipidemia, hyper-cholesterolemia, hypertriglyceridemia, lipidmetabolism disorder, atherosclerosis, hypertension, congestive heartfailure, edema, hyperuricemia and gout;

[20] an agent for the inhibition of advancing impaired glucose toleranceor impaired fasting glycemia into diabetes in a subject, which comprisesas an active ingredient a pyrazole derivative described in any one ofthe above [1]-[14], a pharmaceutically acceptable salt thereof or aprodrug thereof;

[21] an agent for the prevention or treatment of a disease associatedwith the increase of blood galactose level, which comprises as an activeingredient a pyrazole derivative described in any one of the above[1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof;

[22] an agent for the prevention or treatment described in the above[21] wherein the disease associated with the increase of blood galactoselevel is galactosemia;

[23] a pharmaceutical composition described in the above [15] whereinthe dosage form is sustained release formulation;

[24] an agent described in any one of the above [16]-[22] wherein thedosage form is sustained release formulation;

[25] a method for the prevention or treatment of a disease associatedwith hyperglycemia, which comprises administering an effective amount ofa pyrazole derivative described in any one of the above [1]-[14], apharmaceutically acceptable salt thereof or a prodrug thereof;

[26] a method for the inhibition of advancing impaired glucose toleranceinto diabetes in a subject, which comprises administering an effectiveamount of a pyrazole derivative described in any one of the above[1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof;

[27] a use of a pyrazole derivative described in any one of the above[1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof for the manufacture of a pharmaceutical composition for theprevention or treatment of a disease associated with hyperglycemia;

[28] a use of a pyrazole derivative described in any one of the above[1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof for the manufacture of a pharmaceutical composition for theinhibition of advancing impaired glucose tolerance into diabetes in asubject;

[29] a pharmaceutical combination which comprises (A) a pyrazolederivative described in any one of the above [1]-[14], apharmaceutically acceptable salt thereof or a prodrug thereof, and (B)at least one member selected from the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationend products formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer;

[30] a method for the prevention or treatment of a disease associatedwith hyperglycemia, which comprises administering an effective amount of(A) a pyrazole derivative described in any one of the above [1]-[14], apharmaceutically acceptable salt thereof or a prodrug thereof, and (B)at least one member selected from the group consisting of an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer;

[31] a method for the inhibition of advancing impaired glucose toleranceinto diabetes in a subject, which comprises administering an effectiveamount of (A) a pyrazole derivative described in any one of the above[1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof, and (B) at least one member selected from the group consistingof an insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer;

[32] a use of (A) a pyrazole derivative described in any one of theabove [1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof, and (B) at least one member selected from the group consistingof an insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer, for the manufacture of a pharmaceutical composition for theprevention or treatment of a disease associated with hyperglycemia;

[33] a use of (A) a pyrazole derivative described in any one of theabove [1]-[14], a pharmaceutically acceptable salt thereof or a prodrugthereof, and (B) at least one member selected from the group consistingof an insulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer, for the manufacture of a pharmaceutical composition for theinhibition of advancing impaired glucose tolerance into diabetes in asubject;

[34] a pyrazole derivative represented by the general formula:

wherein

R¹¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a hydroxy(C₂₋₆ alkyl) group which may have a protective group, aC₃₋₇ cycloalkyl group, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group,an aryl group which may have the same or different 1 to 3 substituentsselected from the group consisting of a halogen atom, a hydroxy groupwhich may have a protective group, an amino group which may have aprotective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, or anaryl(C₁₋₆ alkyl) group which may have the same or different 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group which may have a protective group, an amino group whichmay have a protective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy groupon the ring;

one of Q² and T² represents a2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group or a2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy group, while the otherrepresents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group, a C₁₋₆alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group;

R¹² represents a hydrogen atom, a halogen atom, a hydroxy group whichmay have a protective group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, aC₁₋₆ alkylthio group, a halo(C₁₋₆ alkyl) group, a halo(C₁₋₆ alkoxy)group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkoxy) group, a C₃₋₇cycloalkyl-substituted (C₂₋₆ alkoxy) group or a group of the generalformula: -A-R¹⁸ in which A represents a single bond, an oxygen atom, amethylene group, an ethylene group, —OCH₂— or —CH₂O—; and R¹⁸ representsa C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl groupwhich may have the same or different 1 to 3 substituents selected fromthe group consisting of a halogen atom, a hydroxy group which may have aprotective group, an amino group which may have a protective group, aC₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group, ahalo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have aprotective group, a carboxy group which may have a protective group, aC₂₋₇ alkoxycarbonyl group, a cyano group and a nitro group, or aheteroaryl group which may have a substituent selected from the groupconsisting of a halogen atom and a C₁₋₆ alkyl group;

X represents a single bond, an oxygen atom or a sulfur atom;

Y represents a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylenegroup with the proviso that X is a single bond when Y is a single bond;

Z represents a carbonyl group or a sulfonyl group;

R¹⁴ and R¹⁵ are the same or different, and each represents a hydrogenatom or a C₁₋₆ alkyl group which may have the same or different 1 to 3groups selected from the following substituent group (ii), or they bindtogether with the neighboring nitrogen atom to form a C₂₋₆ cyclic aminogroup which may have a substituent selected from the group consisting ofa C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group which may have aprotective group;

R³, R⁶ and R⁷ are the same or different, and each represents a hydrogenatom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group; and

substituent group (ii) consists of a hydroxy group which may have aprotective group, an amino group which may have a protective group, amono or di(C₁₋₆ alkyl)amino group which may have a protective group, amono or di[hydroxy(C₁₋₆ alkyl)]amino group which may have a protectivegroup, an ureido group, a sulfamide group, a mono or di(C₁₋₆alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a C₂₋₇acylamino group, a C₁₋₆ alkylsulfonylamino group, a group of the generalformula: —CON(R¹⁹)R²⁰ in which R¹⁹ and R²⁰ are the same or different,and each represents a hydrogen atom or a C₁₋₆ alkyl group which may havethe same or different 1 to 3 substituents selected from the groupconsisting of a hydroxy group which may have a protective group, anamino group which may have a protective group, a mono or di(C₁₋₆alkyl)amino group which may have a protective group, a mono ordi[hydroxy(C₁₋₆ alkyl)]amino group which may have a protective group, anureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylaminogroup, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or theybind together with the neighboring nitrogen atom to form a C₂₋₆ cyclicamino group which may have a substituent selected from the groupconsisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group whichmay have a protective group, a C₃₋₇ cycloalkyl group, a C₂₋₆heterocycloalkyl group, an aryl group which may have the same ordifferent 1 to 3 substituents selected from the group consisting of ahalogen atom, a hydroxy group which may have a protective group, anamino group which may have a protective group, a C₁₋₆ alkyl group and aC₁₋₆ alkoxy group, a heteroaryl group which may have a substituentselected from the group consisting of a halogen atom and a C₁₋₆ alkylgroup, a C₂₋₆ cyclic amino group which may have a substituent selectedfrom the group consisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆alkyl) group which may have a protective group, and a C₁₋₄ aromaticcyclic amino group which may have a C₁₋₆ alkyl group as a substituent,or a salt thereof; and the like.

In the present invention, the term “C₁₋₆ alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “C₁₋₆ alkylene group” means astraight-chained or branched alkylene group having 1 to 6 carbon atomssuch as a methylene group, an ethylene group, a trimethylene group, atetramethylene group, a propylene group, a 1,1-dimethylethylene group orthe like; the term “hydroxy(C₁₋₆ alkyl) group” means the above C₁₋₆alkyl group substituted by a hydroxy group; the term “C₂₋₆ alkyl group”means a straight-chained or branched alkyl group having 2 to 6 carbonatoms such as an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “hydroxy(C₂₋₆ alkyl) group”means the above C₂₋₆ alkyl group substituted by a hydroxy group, such asa 2-hydroxyethyl group, a 3-hydroxypropyl group or the like; the term“C₁₋₆ alkoxy group” means a straight-chained or branched alkoxy grouphaving 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group, a butoxy group, an isobutoxy group,a sec-butoxy group, a tert-butoxy group, a pentyloxy group, anisopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, ahexyloxy group or the like; the term “C₁₋₆ alkoxy-substituted (C₁₋₆alkyl) group” means the above C₁₋₆ alkyl group substituted by the aboveC₁₋₆ alkoxy group; the term “C₁₋₆ alkoxy-substituted (C₁₋₆ alkoxy)group” means the above C₁₋₆ alkoxy group substituted by the above C₁₋₆alkoxy group, such as a methoxymethoxy group or the like; the term “C₂₋₆alkenyl group” means a straight-chained or branched alkenyl group having2 to 6 carbon atoms such as a vinyl group, an allyl group, a 1-propenylgroup, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a2-methylallyl group or the like; the term “C₂₋₆ alkenylene group” meansa straight-chained or branched alkenylene group having 2 to 6 carbonatoms such as a vinylene group, a propenylene group or the like; theterm “C₂₋₆ alkenyloxy group” means the above C₁₋₆ alkoxy group exceptfor a methoxy group which has an unsaturated bond, such as an allyloxygroup or the like; the term “C₁₋₆ alkylthio group” means astraight-chained or branched alkylthio group having 1 to 6 carbon atomssuch as a methylthio group, an ethylthio group, a propylthio group, anisopropylthio group, a butylthio group, an isobutylthio group, asec-butylthio group, a tert-butylthio group, a pentylthio group, anisopentylthio group, a neopentylthio group, a tert-pentylthio group, ahexylthio group or the like; the term “mono or di(C₁₋₆ alkyl)aminogroup” means an amino group mono-substituted by the above C₁₋₆ alkylgroup or di-substituted by the same or different C₁₋₆ alkyl groups asdefined above; the term “mono or di[hydroxy(C₁₋₆ alkyl)]amino group”means an amino group mono-substituted by the above hydroxy(C₁₋₆ alkyl)group or di-substituted by the same or different hydroxy(C₁₋₆ alkyl)groups as defined above; the term “mono or di(C₁₋₆ alkyl)ureido group”means an ureido group mono-substituted by the above C₁₋₆ alkyl group ordi-substituted by the same or different C₁₋₆ alkyl groups as definedabove; the term “mono or di(C₁₋₆ alkyl)sulfamide group” means asulfamide group mono-substituted by the above C₁₋₆ alkyl group ordi-substituted by the same or different C₁₋₆ alkyl groups as definedabove; the term “C₂₋₇ acylamino group” means an amino group substitutedby a straight-chained or branched acyl group having 2 to 7 carbon atomssuch as an acetyl group, a propionyl group, a butyryl group, anisobutyryl group, a valeryl group, a pivaloyl group, a hexanoyl group orthe like; the term “C₁₋₆ alkylsulfonylamino group” means an amino groupsubstituted by a straight-chained or branched alkylsulfonyl group having1 to 6 carbon atoms, such as a methanesulfonyl group, an ethane-sulfonylgroup or the like; the term “C₃₋₇ cycloalkyl group” means a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or acycloheptyl group; the term “C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl)group” means the above C₁₋₆ alkyl group substituted by the above C₃₋₇cycloalkyl group; the term “C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy)group” means the above C₁₋₆ alkoxy group except for a methoxy groupsubstituted by the above C₃₋₇ cycloalkyl group; the term “C₂₋₆heterocyclo-alkyl group” means the above C₃₋₇ cycloalkyl groupcontaining the same or different 1 or 2 hetero atoms other than thebinding position selected from a nitrogen atom, an oxygen atom and asulfur atom in the ring, which is derived from morpholine,thiomorpholine, tetrahydrofuran, tetrahydropyran, aziridine, azetidine,pyrrolidine, imidazolidine, oxazoline, piperidine, piperazine,pyrazolidine or the like; the term “halogen atom” means a fluorine atom,a chlorine atom, a bromine atom or an iodine atom; the term “halo(C₁₋₆alkyl) group” means the above C₁₋₆ alkyl group substituted by the sameor different 1 to 5 halogen atoms as defined above, such as atrifluoromethyl group, a pentafluoroethyl group or the like; the term“halo(C₁₋₆ alkoxy) group” means the above C₁₋₆ alkoxy group substitutedby the same or different 1 to 5 halogen atoms as defined above; the term“C₂₋₇ alkoxycarbonyl group” means a straight-chained or branchedalkoxycarbonyl group having 2 to 7 carbon atoms such as amethoxycarbonyl group, an ethoxycarbonyl group, a propoxy-carbonylgroup, an isopropoxycarbonyl group, a butoxycarbonyl group, anisobutyloxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, a pentyloxycarbonyl group, anisopentyloxycarbonyl group, a neopentyloxycarbonyl group, atert-pentyloxycarbonyl group, a hexyloxycarbonyl group or the like; theterm “aryl group” means mono to tricyclic aromatic hydrocarbon groupsuch as a phenyl group, a naphthyl group, or the like; the term“aryl(C₁₋₆ alkyl) group” means the above C₁₋₆ alkyl group substitute bythe above aryl group; the term “heteroaryl group” means a 5 or6-membered heteroaryl group containing the same or differenr 1 to 4hetero atoms other than the binding position selected from a nitrogenatom, an oxygen atom and a sulfur atom in the ring, which is derivedfrom thiazole, oxazole, isothiazole, isooxazole, pyridine, pyrimidine,pyrazine, pyridazine, pyrrole, thiophene, imidazole, pyrazole,oxadiazole, thiodiazole, tetrazole, furazan or the like; the term “C₂₋₆cyclic amino group” means a 5 or 6-membered monocyclic amino grouphaving 2 to 6 carbon atoms which may contain one hetero atom other thanthe nitrogen atom at the binding position selected from a nitrogen atom,an oxygen atom and a sulfur atom in the ring, such as a morpholinogroup, a thiomorpholino group, a 1-aziridinyl group, a 1-azetidinylgroup, a 1-pyrrolidinyl group, a piperidino group, a 1-imidazolidinylgroup, a 1-piperazinyl group, a pyrazolidinyl group or the like; theterm “C₁₋₄ aromatic cyclic amino group” means a 5-membered aromaticmonocyclic amino group having 1 to 4 carbon atoms which may contain 1 to3 nitrogen atoms other than the nitrogen atom at the binding position,such as a 1-imidazolyl group, a 1-pyrrolyl group, a pyrazolyl group, a1-tetrazolyl group or the like; the term “hydroxy-protective group”means a hydroxy-protective group used in general organic synthesis suchas a benzyl group, a methoxymethyl group, an acetyl group, a pivaloylgroup, a benzoyl group, a tert-butyldimethylsilyl group, atriisopropylsilyl group, an allyl group or the like; the term“amino-protective group” means an amino-protective group used in generalorganic synthesis such as a benzyloxycarbonyl group, atert-butoxy-carbonyl group, a benzyl group, a trifluoroacetyl group orthe like; and the term “carboxy-protective group” means acarboxy-protective group used in general organic synthesis such as abenzyl group, a tert-butyldimethylsilyl group, an allyl group or thelike.

In the present invention, for example, R¹ is preferably a hydrogen atomor a hydroxy(C₂₋₆ alkyl) group, and is more preferably a hydrogen atom;T is preferably a group of the formula:

or a group of the formula:

Q is preferably a C₁₋₆ alkyl group or a halo(C₁₋₆ alkyl) group, and ismore preferably a C₁₋₆ alkyl group; the C₁₋₆ alkyl group in Q ispreferably an ethyl group or an isopropyl group, and is more preferablyan isopropyl group; X is preferably a single bond or an oxygen atom.Furthermore, when X is a single bond, Y is preferably a C₁₋₆ alkylenegroup or a C₂₋₆ alkenylene group, and is more preferably a trimethylenegroup or a 1-propenylene group; and when X is an oxygen atom, Y ispreferably a C₁₋₆ alkylene group, and is more preferably an ethylenegroup or a trimethylene group. Z is preferably a carbonyl group; R² ispreferably a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆alkoxy group, a C₁₋₆ alkoxy-substituted (C₂₋₆ alkoxy) group, a C₃₋₇cycloalkyl-substituted (C₂₋₆ alkoxy) group or a group of the generalformula: -A-R⁸ in which A and R⁸ have the same meanings as definedabove, and is more preferably a hydrogen atom, a chlorine atom, afluorine atom or a methyl group; one of R⁴ and R⁵ is preferably a C₁₋₆alkyl group which has 1 to 3 hydroxy groups or a group of the generalformula: —CON(R⁹)R¹⁰ in which R⁹ and R¹⁰ are the same or different, andeach represents a hydrogen atom or a C₁₋₆ alkyl group which may have thesame or different 1 to 3 substituents selected from the group consistingof a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group,a mono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono ordi(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆alkylsulfonylamino group and a carbamoyl group, or they bind togetherwith the neighboring nitrogen atom to form a C₂₋₆ cyclic amino groupwhich may have a substituent selected from the group consisting of aC₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, while the other ispreferably a hydrogen atom, and one of R⁴ and R⁵ is more preferably aC₁₋₆ alkyl group which has a group of the general formula:—CON(R^(9A))R^(10A) in which R^(9A) and R^(10A) bind together with theneighboring nitrogen atom to form a C₂₋₆ cyclic amino group which mayhave a substituent selected from the group consisting of a C₁₋₆ alkylgroup and a hydroxy(C₁₋₆ alkyl) group, while the other is morepreferably a hydrogen atom; and R³, R⁶ and R⁷ are preferably a hydrogenatom or a halogen atom, and all of them are more preferably a hydrogenatom.

As concrete compounds in the present invention, compounds described inExamples 1-116 are exemplified. Specifically, the following compounds orpharmaceutically acceptable salts thereof are preferable,

and3-(β-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]-methyl}-1H-pyrazole;3-(β-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl-carbamoyl}propyl)phenyl]methyl}-1H-pyrazole;3-(β-D-gluco-pyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}ethoxy)-2-methyl-phenyl]methyl}-1H-pyrazole;3-(β-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyrazole;3-(β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)-2-methylphenyl]methyl}-1H-pyrazole;3-(β-D-gluco-pyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)-carbonyl]-1-(methyl)ethylcarbamoyl}propoxy)-2-methyl-phenyl]methyl}-1H-pyrazole;3-(β-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-pyrazole;4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole,or pharmaceutically acceptable salts thereof are more preferable.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared according to the followingprocedure:

wherein L¹ represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group or the like; L² represents MgBr, MgCl, MgI, ZnI,ZnBr, ZnCl or a lithium atom; R represents a C₁₋₆ alkyl group, ahalo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group ora C₃₋₇ cycloalkyl group; R⁰ represents a C₁₋₆ alkyl group; one of Q³ andT³ represents a hydroxy group, the other represents a C₁₋₆ alkyl group,a halo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) groupor a C₃₋₇ cycloalkyl group; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, R¹²,R¹⁴, R¹⁵, Q, Q², T, T², X, Y and Z have the same meanings as definedabove.Process 1-1

A compound represented by the above general formula (VI) can be preparedby condensing a benzyl derivative represented by the above generalformula (IV) with a ketoacetate represented by the above general formula(V) in the presence of a base such as sodium hydride or potassiumtert-butoxide in an inert solvent. As the inert solvent used in thereaction, for example, 1,2-dimethoxyethane, tetrahydrofuran,N,N-dimethylformamide, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature.

Process 1-2

A benzylpyrazole derivative represented by the above general formula(III) can be prepared by condensing a compound represented by the abovegeneral formula (VI) with a hydrazine compound represented by the abovegeneral formula (VII) or a monohydrate thereof, or a salt thereof in thepresence or absence of a base in an inert solvent, and introducing ahydroxy-protective in usual way as occasion demands. As the inertsolvent used in the condensing reaction, for example, toluene,tetrahydrofuran, chloroform, methanol, ethanol, a mixed solvent thereofand the like can be illustrated, and as tha base, for example,triethylamine, N,N-diisopropylethylamine, pyridine, sodium methoxide,sodium ethoxide and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature. The obtainedbenzylpyrazole derivative represented by the above general formula (III)can be also used in the subsequent process after suitably convertinginto a salt thereof in usual way.

Process 1-3

A compound represented by the above general formula (X) can be preparedby condensing dithiocarbonate ester compound represented by the abovegeneral formula (VIII) with a ketone compound represented by the abovegeneral formula (IX) in the presence of a base such as sodium amide inan inert solvent. As the inert solvent used in the reaction, forexample, toluene and the like can be illustrated. The reactiontemperature is usually from −20° C. to room temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process 1-4

A benzyloxypyrazole derivative represented by the above general formula(XI) can be prepared by condensing a compound represented by the abovegeneral formula (X) with a hydrazine compound represented by the abovegeneral formula (VII) or a monohydrate thereof, or a salt thereof in thepresence of a base such as triethylamine or N,N-diisopropylethylamine inan inert solvent, and introducing a hydrogen-protective in usual way asoccasion demands. As the inert solvent used in the condensing reaction,for example, acetonitrile and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 1 hour to 1 day, varying based on a usedstarting material, solvent and reaction temperature.

Process 1-5

A pyrazole aldehyde derivative represented by the above general formula(XII) can be prepared by subjecting a compound represented by the abovegeneral formula (XI) to Vilsmeier reaction using phosphorus oxychlorideand N,N-dimethyl-formamide in a various solvent. As the solvent used inthe reaction, for example, N,N-dimethylformamide and the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process 1-6

A compound represented by the above general formula (XIV) can beprepared by condensing a compound represented by the above generalformula (XII) with a Grignard reagent, a Reformatsky reagent or alithium reagent represented by the above general formula (XIII) in aninert solvent. As the solvent used in the reaction, for example,tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like canbe illustrated. The reaction temperature is usually from −78° C. to roomtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process 1-7

A benzylpyrazole derivative represented by the above general formula(III) can be prepared by subjecting a compound represented by the abovegeneral formula (XIV) to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon powder in the presence or absence ofan acid such as hydrochloric acid in an inert solvent, and in a case ofa compound having any sulfur atom represented by the above generalformula (XIV), subjecting the resulting compound to acid treatment in anaqueous solution of trifluoroacetic acid and dimethyl sulfide usually at0° C. to reflux temperature for 30 minutes to 1 day as occasion demands.As the solvent used in the catalytic hydrogenation, for example,methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid,isopropanol, a mixed solvent thereof and the like can be illustrated.The reaction temperature is usually from room temperature to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. The obtained benzylpyrazole derivative represented by theabove general formula (III) can be also used in the subsequent processafter suitably converting into a salt thereof in the usual way.

Process 1-8

-   [1] In case that one of Q³ and T³ is a C₁₋₆ alkyl group, a C₁₋₆    alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group in    a benzylpyrazole derivative represented by the above general formula    (III), a corresponding compound represented by the above general    formula (II) of the present invention can be prepared by subjecting    a corresponding benzylpyrazole derivative represented by the above    general formula (III) to glycosidation using acetobromo-α-D-glucose    or acetobromo-α-D-galactose in the presence of a base such as silver    carbonate, sodium hydride or the like in an inert solvent. As the    inert solvent used in the reaction, for example, tetrahydrofuran,    dimethoxyethane, N,N-dimethylformamide, a mixed solvent thereof and    the like can be illustrated. The reaction temperature is usually    from room temperature to reflux temperature, and the reaction time    is usually from 1 hour to 1 day, varying based on a used starting    material, solvent and reaction temperature.-   [2] In case that one of Q³ and T³ is a halo(C₁₋₆ alkyl) group in a    benzylpyrazole derivative represented by the above general formula    (III), a corresponding compound represented by the above general    formula (II) of the present invention can be prepared by subjecting    a corresponding benzylpyrazole derivative represented by the above    general formula (III) to glycosidation using acetobromo-α-D-glucose    or acetobromo-α-D-galactose in the presence of a base such as    potassium carbonate or the like in an inert solvent. As the inert    solvent used in the reaction, for example, tetrahydrofuran,    acetonitrile, a mixed solvent thereof and the like can be    illustrated. The reaction temperature is usually from room    temperature to reflux temperature, and the reaction time is usually    from 1 hour to 1 day, varying based on a used starting material,    solvent and reaction temperature.-   [3] In case that one of Q³ and T³ is a C₂₋₆ alkyl group, a C₁₋₆    alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group in    a benzylpyrazole derivative represented by the above general formula    (III), a corresponding compound represented by the above general    formula (II) of the present invention can be also prepared by    subjecting a corresponding benzylpyrazole derivative represented by    the above general formula (III) to glycosidation using    acetobromo-α-D-glucose or acetobromo-α-D-galactose in the presence    of a base such as sodium hydroxide, potassium hydroxide, potassium    carbonate or the like and a phase transfer catalyst such as    benzyltri(n-butyl)ammonium chloride, benzyltri(n-butyl)ammonium    bromide, tetra(n-butyl)ammonium hydrogen sulfate or the like in an    inert solvent containing water. As the inert solvent used in the    reaction, dichloromethane, toluene, benzotrifluoride, a mixed    solvent thereof and the like can be illustrated. The reaction    temperature is usually from 0° C. to reflux temperature, and the    reaction time is usually from 30 minutes to 1 day, varying based on    a used starting material, solvent and reaction temperature.

The obtained glycosidated benzylpyrazole derivative represented by theabove general formula (II) can be also used in the subsequent processafter suitably converting into a salt thereof and separating in theusual way.

Process 1-9

A pyrazole derivative represented by the above general formula (I) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (II) to alkaline hydrolysis,and removing a protective group or subjecting a nitro group of theresulting compound to reduction as occasion demands. As the solvent usedin the hydrolysis reaction, for example, methanol, ethanol,tetrahydrofuran, water, a mixed solvent thereof and the like can beillustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature. As mentionedabove, in case of compounds having a protective group in R¹¹, R¹², R¹⁴and/or R¹⁵ after the hydrolysis, the protective group can be suitablyremoved in the usual way. Furthermore, after the completion of the abovereaction, compounds having a nitro group in R² represented by the abovegeneral formula (I) can be also derived into a corresponding compoundhaving an amino group by catalytic reduction using a platinum catalystsuch as platinum oxide in an inert solvent such as ethyl acetate atusually room temperature to reflux temperature for usually 30 minutes to1 day in the usual way.

Among the compounds represented by the above general formula (III) asstarting materials, there can be the following three tautomers incompounds wherein R¹¹ is a hydrogen atom, varying based on difference inthe reaction conditions, and the compounds represented by the abovegeneral formula (III) include all the compounds:

wherein R, R³, R⁶, R⁷, R¹², R¹⁴, R¹⁵, X, Y and Z have the same meaningsas defined above.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkylgroup, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group or anaryl-substituted (C₁₋₆ alkyl) group which may have the same or different1 to 3 substituents selected from the group consisting of a halogenatom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆alkoxy group, for example, can be prepared according to the followingprocedure:

wherein L³ represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group or the like; R²¹ represents a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group which may have aprotective group, a C₃₋₇ cycloalkyl group, a C₃₋₇ cycloalkyl-substituted(C₁₋₆ alkyl) group or an aryl-substituted (C₁₋₆ alkyl) group which mayhave the same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group which may have aprotective group, an amino group which may have a protective group, aC₁₋₆ alkyl group and a C₁₋₆ alkoxy group; R³¹ represents a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇cycloalkyl group, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group or anaryl-substituted (C₁₋₆ alkyl) group which may have the same or different1 to 3 substituents selected from the group consisting of a halogenatom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆alkoxy group; and R², R³, R⁴, R⁵R⁶, R⁷, R¹², R¹⁴, R¹⁵, Q, Q², T, T², X,Y and Z have the same meanings as defined above.Process 2

A pyrazole derivative represented by the above general formula (Ia) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIa) to hydrolysis accordingto a similar method to that described in the above process 1-9 andN-alkylation using an N-alkylating agent represented by the abovegeneral formula (XV) in the presence of a base such as cesium carbonateor potassium carbonate in an inert solvent, and in case of compoundshaving a protective group, suitably removing the protective group in theusual way as occasion demands. As the inert solvent used in theN-alkylation, for example, acetonitrile, ethanol, 1,2-dimethoxyethane,tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a hydrogen atom, forexample, can be also prepared according to the following procedure:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R¹², R¹⁴, R¹⁵, Q, Q², T, T², X, Y and Zhave the same meanings as defined above.Process 3-1

A compound represented by the above general formula (XVII) can beprepared by subjecting a compound represented by the above generalformula (XVI) to catalytic hydrogenation using a palladium catalyst suchas palladium-carbon powder in an inert solvent to remove the benzylgroup. As the solvent used in the catalytic hydrogenation, for example,methanol, ethanol, tetrahydrofuran, ethyl acetate, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from 0° C. to reflux temperature, and the reaction time isusually from 1 hour to 2 days, varying based on a used startingmaterial, solvent and reaction temperature.

Process 3-2

A compound represented by the above general formula (IIa) of the presentinvention can be prepared by condensing a compound represented by theabove general formula (XVII) with an amine derivative represented by theabove general formula (XVIII) in the presence of a condensing agent suchas 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride ordicyclohexyl-carbodiimide and in the presence or absence of a base suchas triethylamine or N,N-diisopropylethylamine in an inert solvent aftersuitably adding 1-hydroxybenzotriazole as occasion demands. As thesolvent used in the condensing reaction, for example,N,N-dimethylformamide, dichloromethane, tetra-hydrofuran, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 1 hour to 2 days, varying based on a usedstarting material, solvent and reaction temperature.

Process 3-3

A pyrazole derivative represented by the above general formula (Ib) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIa) to alkaline hydrolysis,and removing the protective group in the usual way as occasion demands.As the solvent used in the hydrolysis reaction, for example, methanol,ethanol, tetrahydrofuran, water, a mixed solvent thereof and the likecan be illustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature. In case ofcompounds having a protective group in R¹², R¹⁴ and/or R¹⁵ after thehydrolysis, the protective group can be suitably removed in the usualway as the process 1-9.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a hydrogen atom; Xrepresents a single bond; and Y represents a C₂₋₆ alkylene group or aC₂₋₆ alkenylene group, for example, can be prepared according to thefollowing procedures:

wherein L⁴ represents a leaving group such as a chlorine atom, a bromineatom, an iodine atom, a trifluoromethanesulfonyloxy group or the like;Y¹ represents a single bond or a C₁₋₄ alkylene group; and R², R³, R⁴,R⁵, R⁶, R⁷, R¹², R¹⁴, R¹⁵, Q, Q², T, T² and Z have the same meanings asdefined above.Process 4-1

A pyrazole derivative represented by the above general formula (XXI) canbe prepared by subjecting a pyrazole derivative represented by the abovegeneral formula (XIX) to Heck reaction with an olefine derivativerepresented by the above general formula (XX) using a palladium catalystsuch as palladium-carbon powder, palladium acetate,tetrakis(triphenylphosphine)-palladium, dibenzylidene acetone palladiumor bis(triphenyl-phosphine)palladium dichloride in the presence orabsence of a phosphine ligand such as tris(2-methylphenyl)phosphine ortriphenylphosphine and in the presence of a base such as triethylamine,sodium tert-butoxide, potassium tert-butoxide or cesium fluoride in aninert solvent. As the solvent used in the reaction, for example,acetonitrile, toluene, tetrahydrofuran, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from 0° C.to reflux temperature, and the reaction time is usually from 1 hour to 2days, varying based on a used starting material, solvent and reactiontemperature.

Process 4-2

A compound represented by the above general formula (XXII) can beprepared by subjecting a compound represented by the above generalformula (XXI) to catalytic hydrogenation using a palladium catalyst suchas palladium-carbon powder in an inert solvent. As the solvent used inthe catalytic hydrogenation, for example, methanol, ethanol,tetrahydrofuran, ethyl acetate, a mixed solvent thereof and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 1 hour to 2 days,varying based on a used starting material, solvent and reactiontemperature.

Process 4-3

A compound represented by the above general formula (IIb) of the presentinvention can be prepared by condensing a compound represented by theabove general formula (XXII) with an amine derivative represented by theabove general formula (XVIII) in the presence of a condensing agent suchas 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride ordicyclohexyl-carbodiimide and a base such as triethylamine orN,N-diisopropyl-ethylamine in an inert solvent after suitably adding1-hydroxy-benzotriazole as occasion demands, and suitably removing theprotective group in the usual way as occasion demands. As the solventused in the condensing reaction, for example, N,N-dimethylformamide,dichloromethane, tetrahydrofuran, a mixed solvent thereof and the likecan be illustrated. The reaction temperature is usually from 0° C. toreflux temperature, and the reaction time is usually from 1 hour to 2days, varying based on a used starting material, solvent and reactiontemperature.

Process 4-4

A pyrazole derivative represented by the above general formula (Ic) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIb) to alkaline hydrolysis,and suitably removing the protective group in the usual way as occasiondemands. As the solvent used in the hydrolysis reaction, for example,methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof andthe like can be illustrated. As the base, for example, sodium hydroxide,sodium methoxide, sodium ethoxide and the like can be illustrated. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. In case ofcompounds having a protective group in R¹², R¹⁴ and/or R¹⁵ after thehydrolysis, the protective group can be suitably removed in the usualway as the process 1-9.

In the formula, L⁴, R², R³, R⁴, R⁵, R⁶, R⁷, R¹², R¹⁴, R¹⁵, Q, Q², T, T²,Y¹ and Z have the same meanings as defined above.Process 5-1

A compound represented by the above general formula (IIc) of the presentinvention can be prepared by condensing a compound represented by theabove general formula (XXI) with an amine derivative represented by theabove general formula (XVIII) in the presence of a condensing agent suchas 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride ordicyclohexyl-carbodiimide and a base such as triethylamine orN,N-diisopropyl-ethylamine in an inert solvent after suitably adding1-hydroxy-benzotriazole as occasion demands, and suitably removing theprotective group in the usual way as occasion demands. As the solventused in the condensing reaction, for example, N,N-dimethylformamide,dichloromethane, tetrahydrofuran, a mixed solvent thereof and the likecan be illustrated. The reaction temperature is usually from 0° C. toreflux temperature, and the reaction time is usually from 1 hour to 2days, varying based on a used starting material, solvent and reactiontemperature.

Process 5-2

A pyrazole derivative represented by the above general formula (IIc) ofthe present invention can be prepared by subjecting a pyrazolederivative represented by the above general formula (XIX) to Heckreaction with an olefine derivative represented by the above generalformula (XXIII) using a palladium catalyst such as palladium-carbonpowder, palladium acetate, tetrakis(triphenylphosphine)palladium,dibenzylideneacetonepalladium or bis(triphenylphosphine)-palladiumdichloride in the presence or absence of a phosphine ligand such astris(2-methylphenyl)phosphine or triphenyl-phosphine and in the presenceof a base such as triethylamine, sodium tert-butoxide, potassiumtert-butoxide or cesium fluoride in an inert solvent. As the solventused in the reaction, for example, acetonitrile, toluene,tetrahydrofuran, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 1 hour to 2 days,varying based on a used starting material, solvent and reactiontemperature.

Process 5-3

A pyrazole derivative represented by the above general formula (Id) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIc) to alkaline hydrolysis,and suitably removing the protective group in the usual way as occasiondemands. As the solvent used in the hydrolysis reaction, for example,methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof andthe like can be illustrated. As the base, for example, sodium hydroxide,sodium methoxide, sodium ethoxide and the like can be illustrated. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. In case ofcompounds having a protective group in R¹², R¹⁴ and/or R¹⁵ after thehydrolysis, the protective group can be suitably removed in the usualway as the process 1-9.

Process 5-4

A compound represented by the above general formula (IIb) can beprepared by subjecting a compound represented by the above generalformula (IIc) to catalytic hydrogenation using a palladium catalyst suchas palladium-carbon powder in an inert solvent. As the solvent used inthe catalytic hydrogenation, for example, methanol, ethanol,tetrahydrofuran, ethyl acetate, a mixed solvent thereof and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 1 hour to 2 days,varying based on a used starting material, solvent and reactiontemperature.

Process 5-5

A compound represented by the above general formula (Ic) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (Id) to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon powder in an inert solvent. As thesolvent used in the catalytic hydrogenation, for example, methanol,ethanol, tetrahydrofuran, ethyl acetate, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from 0° C.to reflux temperature, and the reaction time is usually from 1 hour to 2days, varying based on a used starting material, solvent and reactiontemperature.

Process 5-6

A pyrazole derivative represented by the above general formula (Ic) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIb) to alkaline hydrolysis,and suitably removing the protective group in the usual way as occasiondemands. As the solvent used in the hydrolysis reaction, for example,methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof andthe like can be illustrated. As the base, for example, sodium hydroxide,sodium methoxide, sodium ethoxide and the like can be illustrated. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. In case ofcompounds having a protective group in R¹², R¹⁴ and/or R¹⁵ after thehydrolysis, the protective group can be suitably removed in the usualway as the process 1-9.

The compounds represented by the above general formula (I) of thepresent invention obtained by the above production processes can beisolated and purified by conventional separation means such asfractional recrystallization, purification using chromatography, solventextraction and solid phase extraction.

The pyrazole derivatives represented by the above general formula (I) ofthe present invention can be converted into their pharmaceuticallyacceptable salts in the usual way. Examples of such salts include acidaddition salts with mineral acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid andthe like, acid addition salts with organic acids such as formic acid,acetic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, propionic acid, citric acid, succinic acid,tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid,maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid,aspartic acid and the like, salts with inorganic bases such as a sodiumsalt, a potassium salt and the like, and salts with organic bases suchas N-methyl-D-glucamine, N,N′-dibenzyletylenediamine, 2-aminoethanol,tris(hydroxy-methyl)aminomethane, arginine, lysine and the like.

The compounds represented by the above general formula (I) of thepresent invention include their solvates with pharmaceuticallyacceptable solvents such as ethanol and water.

Of the pyrazole derivatives represented by the above general formula (I)of the present invention and the prodrugs thereof, there are twogeometrical isomers in each compound having an unsaturated bond. In thepresent invention, either of cis(Z)-isomer or trans(E)-isomer can beemployed.

Of the pyrazole derivatives represented by the above general formula (I)of the present invention and the prodrugs thereof, there are two opticalisomers, R-isomer and S-isomer, in each compound having an asymmetriccarbon atom excluding the glucopyranosyloxy moiety or thegalactopyranosyloxy moiety. In the present invention, either of theisomers can be employed, and a mixture of both isomers can be alsoemployed.

A prodrug of a compound represented by the above general formula (I) ofthe present invention can be prepared by introducing an appropriategroup forming a prodrug into any one or more groups selected from ahydroxy group in the glucopyranosyl moiety or the galactopyranosylmoiety, or optionally in R¹, R², R⁴ or R⁵, a cyclic amino group in casethat R¹ is a hydrogen atom, and an amino group in case that R¹, R², R⁴or R⁵ is a substituent having an amino group of the compound representedby the above general formula (I) using a corresponding reagent toproduce a prodrug such as a halide compound or the like in the usualway, and then by suitably isolating and purificating in the usual way asoccasion demands. As a group forming a prodrug used in a hydroxy groupor an amino group, for example, a C₂₋₇ acyl group, a C₁₋₆alkoxy-substituted (C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl-substituted(C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl group, an aryl-substituted(C₂₋₇ alkoxycarbonyl) group, a C₁₋₆ alkoxy-substituted (C₂₋₇alkoxycarbonyl) group or the like can be illustrated. As a group forminga prodrug used in a cyclic amino group, for example, a C₂₋₇ acyl group,a C₁₋₆ alkoxy-substituted (C₂₋₇ acyl) group, a C₂₋₇alkoxycarbonyl-substituted (C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonylgroup, a C₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group, a (C₂₋₇acyloxy)methyl group, a 1-(C₂₋₇ acyloxy)ethyl group, a (C₂₋₇alkoxycarbonyl)oxymethyl group, a 1-[(C₂₋₇ alkoxycarbonyl)oxy]ethylgroup, a (C₃₋₇ cyclo-alkyl)oxycarbonyloxymethyl group, a 1-[(C₃₋₇cycloalkyl)-oxycarbonyloxy]ethyl group or the like can be illustrated.The term “C₂₋₇ acyl group” means a straight-chained or branched acylgroup having 2 to 7 carbon atoms such as an acetyl group, a propionylgroup, a butyryl group, an isobutyryl group, a valeryl group, a pivaloylgroup, a hexanoyl group or the like; and the term “C₁₋₆alkoxy-substituted (C₂₋₇ acyl) group” means the above C₂₋₇ acyl groupsubstituted by the above C₁₋₆ alkoxy group; the term “C₂₋₇alkoxycarbonyl-substituted (C₂₋₇ acyl) group” means the above C₂₋₇ acylgroup substituted by the above C₂₋₇ alkoxycarbonyl group; the term“aryl-substituted (C₂₋₇ alkoxycarbonyl) group” means the above C₂₋₇alkoxycarbonyl group substituted by the above aryl group, such as abenzyloxycarbonyl group; the term “C₁₋₆ alkoxy-substituted (C₂₋₇alkoxycarbonyl) group” means the above C₂₋₇ alkoxycarbonyl groupsubstituted by the above C₁₋₆ alkoxy group; the term “(C₂₋₇acyloxy)methyl group” means a hydroxymethyl group O-substituted by theabove C₂₋₇ acyl group; the term “1-(C₂₋₇ acyloxy)ethyl group” means a1-hydroxyethyl group O-substituted by the above C₂₋₇ acyl group; theterm “(C₂₋₇ alkoxycarbonyl)oxymethyl group” means a hydroxymethyl groupsubstituted by the above C₂₋₇ alkoxycarbonyl group; and the term“1-[(C₂₋₇ alkoxycarbonyl)oxy]ethyl group” means a 1-hydroxyethyl groupO-substituted by the above C₂₋₇ alkoxycarbonyl group. In addition, theterm “(C₃₋₇ cycloalkyl)oxycarbonyl group” means a cyclic alkoxycarbonylgroup having the above C₃₋₇ cycloalkyl group; the term “(C₃₋₇cycloalkyl)oxycarbonyloxymethyl group” means a hydroxymethyl groupO-substituted by the above (C₃₋₇ cycloalkyl)oxycarbonyl group; and theterm “1-[(C₃₋₇ cycloalkyl)oxycarbonyloxy]ethyl group” means a1-hydroxyethyl group O-substituted by the above (C₃₋₇cycloalkyl)oxycarbonyl group. Furthermore, as a group forming a prodrug,a glucopyranosyl group or a galactopyranosyl group can be illustrated.For example, these groups are preferably introduced into the hydroxygroup at the 4 or 6 position of the glucopyranosyl group or thegalactopyranosyl group, and are more preferably introduced into thehydroxy group at the 4 or 6 position of the glucopyranosyl group.

The pyrazole derivatives represented by the above general formula (I) ofthe present invention, for example, showed a potent inhibitory activityin human SGLT1 in a human SGLT1 inhibitory activity confirmatory test asdescribed below, and exerted an excellent inhibitory activity of bloodglucose level increase in a confirmatory test of the inhibitory activityof blood glucose level increase in rat. Thus, the pyrazole derivativesrepresented by the above general formula (I) of the present inventionexhibit an excellent SGLT1 inhibitory activity at the small intestine,and can remarkably inhibit blood glucose level increase and/or decreaseblood galactose level by inhibiting or delaying glucose and galactoseabsorption. Therefore, a pharmaceutical composition comprising as anactive ingredient a pyrazole derivative represented by the above generalformula (I) of the present invention, a pharmaceutically acceptable saltand a prodrug thereof is extremely useful as an agent for inhibitingpostprandial hypreglycemia, an agent for the inhibition of advancingimpaired glucose tolerance (IGT) or impaired fasting glycemia (IFG) intodiabetes in a subject, and an agent for the prevention or treatment of adisease associated with hyperglycemia such as diabetes, impaired glucosetolerance, impaired fasting glycemia, diabetic complications (e.g.,retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy), obesity,hyperinsulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,hypertension, congestive heart failure, edema, hyperuricemia, gout orthe like, which relates to SGLT1 activity at the small intestine, and anagent for the prevention or treatment of a disease associated withincreasing blood galactose level such as galactosemia.

Furthermore, the compounds of the present invention can be suitably usedin combination with at least one member selected from drugs other thanSGLT2 inhibitors. Examples of the drugs which can be used in combinationwith the compounds of the present invention include an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor (PDGF), a platelet-derivedgrowth factor (PDGF) analogue (e.g., PDGF-AA, PDGF-BB, PDGF-AB),epidermal growth factor (EGF), nerve growth factor, a carnitinederivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol,sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutarylcoenzyme A reductase inhibitor, a fibric acid derivative, aβ₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferaseinhibitor, probcol, a thyroid hormone receptor agonist, a cholesterolabsorption inhibitor, a lipase inhibitor, a microsomal triglyceridetransfer protein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyltransferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.

In case of uses of the compound of the present invention in combinationwith the above one or more drugs, the present invention includes eitherdosage forms of simultaneous administration as a single preparation orseparated preparations in way of the same or different administrationroute, and administration at different dosage intervals as separatedpreparations in way of the same or different administration route. Apharmaceutical combination comprising the compound of the presentinvention and the above drug(s) includes both dosage forms as a singlepreparation and separated preparations for combination as mentionedabove.

The compounds of the present invention can obtain more advantageouseffects than additive effects in the prevention or treatment of theabove diseases when using suitably in combination with the above one ormore drugs. Also, the administration dose can be decreased in comparisonwith administration of either drug alone, or adverse effects ofcoadministrated drugs other than SGLT1 inhibitors can be avoided ordeclined.

Concrete compounds as the drugs used for combination and preferablediseases to be treated are exemplified as follows. However, the presentinvention is not limited thereto, and the concrete compounds includetheir free compounds, and their or other pharmaceutically acceptablesalts.

As insulin sensitivity enhancers, peroxisome proliferator-activatedreceptor-γ agonists such as troglitazone, pioglitazone hydrochloride,rosiglitazone maleate, sodium darglitazone, GI-262570, isaglitazone,LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929,ciglitazone, sodium englitazone and NIP-221, peroxisomeproliferator-activated receptor-α agonists such as GW-9578 andBM-170744, peroxisome proliferator-activated receptor-α/γ agonists suchas GW-409544, KRP-297, N,N-622, CLX-0940, LR-90, SB-219994, DRF-4158 andDRF-MDX8, retinoid X receptor agonists such as ALRT-268, AGN-4204,MX-6054, AGN-194204, LG-100754 and bexarotene, and other insulinsensitivity enhancers such as reglixane, ONO-5816, MBX-102, CRE-1625,FK-614, CLX-0901, CRE-1633, N,N-2344, BM-13125, BM-501050, HQL-975,CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929,AR-H049020 and GW-501516 are illustrated. Insulin sensitivity enhancersare used preferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity, hyperinsulinemia, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder oratherosclerosis, and more preferably for diabetes, impaired glucosetolerance or hyperinsulinemia because of improving the disturbance ofinsulin signal transduction in peripheral tissues and enhancing glucoseuptake into the tissues from the blood, leading to lowering of bloodglucose level.

As glucose absorption inhibitors, compounds other than SGLT1 inhibitors,for example, α-glucosidase inhibitors such as acarbose, voglibose,miglitol, CKD-711, emiglitate, MDL-25,637, camiglibose and MDL-73,945,and α-amylase inhibitors such as AZM-127 are illustrated. Glucoseabsorption inhibitors are used preferably for diabetes, impaired glucosetolerance, diabetic complications, obesity or hyperinsulinemia, and morepreferably for impaired glucose tolerance because of inhibiting thegastrointestinal enzymatic digestion of carbohydrates contained infoods, and inhibiting or delaying the absorption of glucose into thebody.

As biguanides, phenformin, buformin hydrochloride, metforminhydrochloride or the like are illustrated. Biguanides are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications or hyperinsulinemia, and more preferably for diabetes,impaired glucose tolerance or hyperinsulinemia because of lowering bloodglucose level by inhibitory effects on hepatic gluconeogenesis,accelerating effects on anaerobic glycolysis in tissues or improvingeffects on insulin resistance in peripheral tissues.

As insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide,1-butyl-3-metanilyl-urea, carbutamide, glibornuride, glipizide,gliquidone, glisoxapide, glybuthiazol, glybuzole, glyhexamide, sodiumglymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride,nateglinide, mitiglinide calcium hydrate, repaglinide or the like areillustrated. In addition, the insulin secretion enhancers includeglucokinase activators such as RO-28-1675. Insulin secretion enhancersare used preferably for diabetes, impaired glucose tolerance or diabeticcomplications, and more preferably for diabetes or impaired glucosetolerance because of lowering blood glucose level by acting onpancreatic β-cells and enhancing the insulin secretion.

As SGLT2 inhibitors, T-1095 and compounds described in Japanese patentpublications Nos. Hei 10-237089 and 2001-288178, and InternationalPublications Nos. WO01/16147, WO01/27128, WO01/68660, WO01/74834,WO01/74835, WO02/28872, WO02/36602, WO02/44192, WO02/53573 etc. areillustrated. SGLT2 inhibitors are used preferably for diabetes, impairedglucose tolerance, diabetic complications, obesity or hyperinsulinemia,and more preferably for diabetes, impaired glucose tolerance, obesity orhyperinsulinemia because of lowering blood glucose level by inhibitingthe reabsorption of glucose at the kidney's proximal tubule.

As insulin or insulin analogues, human insulin, animal-derived insulin,human or animal-derived insulin analogues or the like are illustrated.These preparations are used preferably for diabetes, impaired glucosetolerance or diabetic complications, and more preferably for diabetes orimpaired glucose tolerance.

As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687 or the likeare illustrated; as insulin receptor kinase stimulants, TER-17411,L-783281, KRX-613 or the like are illustrated; as tripeptidyl peptidaseII inhibitors, UCL-1397 or the like are illustrated; as dipeptidylpeptidase IV inhibitors, NVP-DPP728A, TSL-225, P-32/98 or the like areillustrated; as protein tyrosine phosphatase 1B inhibitors, PTP-112,OC-86839, PNU-177496 or the like are illustrated; as glycogenphosphorylase inhibitors, N,N-4201, CP-368296 or the like areillustrated; as fructose-bisphosphatase inhibitors, R-132917 or the likeare illustrated; as pyruvate dehydrogenase inhibitors, AZD-7545 or thelike are illustrated; as hepatic gluconeogenesis inhibitors, FR-225659or the like are illustrated; as glucagon-like peptide-1 analogues,exendin-4, CJC-1131 or the like are illustrated; as glucagon-likepeptide 1 agonists; AZM-134, LY-315902 or the like are illustrated; andas amylin, amylin analogues or amylin agonists, pramlintide acetate orthe like are illustrated. These drugs, glucose-6-phosphatase inhibitors,D-chiroinsitol, glycogen synthase kinase-3 inhibitors and glucagon-likepeptide-1 are used preferably for diabetes, impaired glucose tolerance,diabetic complications or hyperinsulinemia, and more preferably fordiabetes or impaired glucose tolerance.

As aldose reductase inhibitors, ascorbyl gamolenate, tolrestat,epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598,fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, minalrestat,methosorbinil, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat,AS-3201, NZ-314, SG-210, JTT-811, lindolrestat or the like areillustrated. Aldose reductase inhibitors are preferably used fordiabetic complications because of inhibiting aldose reductase andlowering excessive intracellular accumulation of sorbitol in accelatedpolyol pathway which are in continuous hyperglycemic condition in thetissues in diabetic complications.

As advanced glycation endproducts formation inhibitors, pyridoxamine,OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride or the like areillustrated. Advanced glycation endproducts formation inhibitors arepreferably used for diabetic complications because of inhibitingformation of advanced glycation endproducts which are accelated incontinuous hyperglycemic condition in diabetes and declining of cellulardamage.

As protein kinase C inhibitors, LY-333531, midostaurin or the like areillustrated. Protein kinase C inhibitors are preferably used fordiabetic complications because of inhibiting of protein kinase Cactivity which is accelated in continuous hyperglycemic condition indiabetes.

As γ-aminobutyric acid receptor antagonists, topiramate or the like areillustrated; as sodium channel antagonists, mexiletine hydrochloride,oxcarbazepine or the like are illustrated; as transcrit factor NF-κBinhibitors, dexlipotam or the like are illustrated; as lipid peroxidaseinhibitors, tirilazad mesylate or the like are illustrated; asN-acetylated-α-linked-acid-dipeptidase inhibitors, GPI-5693 or the likeare illustrated; and as carnitine derivatives, carnitine, levacecarninehydrochloride, levocarnitine chloride, levocarnitine, ST-261 or the likeare illustrated. These drugs, insulin-like growth factor-I,platelet-derived growth factor, platelet derived growth factoranalogues, epidermal growth factor, nerve growth factor, uridine,5-hydroxy-1-methyl-hidantoin, EGB-761, bimoclomol, sulodexide and Y-128are preferably used for diabetic complications.

As antidiarrhoics or cathartics, polycarbophil calcium, albumin tannate,bismuth subnitrate or the like are illustrated. These drugs arepreferably used for diarrhea, constipation or the like accompanyingdiabetes or the like.

As hydroxymethylglutaryl coenzyme A reductase inhibitors, sodiumcerivastatin, sodium pravastatin, lovastatin, simvastatin, sodiumfluvastatin, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101,BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987,calcium pitavastatin, calcium rosuvastatin, colestolone, dalvastatin,acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950,glenvastatin, carvastatin, BMY-22089, bervastatin or the like areillustrated. Hydroxymethylglutaryl coenzyme A reductase inhibitors areused preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypercholesterolemia oratherosclerosis because of lowering blood cholesterol level byinhibiting hydroxymethylglutaryl coenzyme A reductase.

As fibric acid derivatives, bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibricacid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate,ronifibrate, simfibrate, theofibrate, AHL-157 or the like areillustrated. Fibric acid derivatives are used preferably forhyperinsulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypertriglyceridemia oratherosclerosis because of activating hepatic lipoprotein lipase andenhancing fatty acid oxidation, leading to lowering of bloodtriglyceride level.

As β₃-adrenoceptor agonists, BRL-28410, SR-58611A, ICI-198157, ZD-2079,BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413,SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552,D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353,N-5984, GW-2696, YM178 or the like are illustrated. β₃-Adrenoceptoragonists are used preferably for obesity, hyperinsulinemia,hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipidmetabolism disorder, and more preferably for obesity or hyperinsulinemiabecause of stimulating β₃-adrenoceptor in adipose tissue and enhancingthe fatty acid oxidation, leading to induction of energy expenditure.

As acyl-coenzyme A cholesterol acyltransferase inhibitors, NTE-122,MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139,CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115,FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8-434, avasimibe,CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E,lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe or thelike are illustrated. Acyl-coenzyme A cholesterol acyltransferaseinhibitors are used preferably for hyperlipidemia,hyper-cholesterolemia, hypertriglyceridemia or lipid metabolismdisorder, and more preferably for hyperlipidemia orhyper-cholesterolemia because of lowering blood cholesterol level byinhibiting acyl-coenzyme A cholesterol acyltransferase.

As thyroid hormone receptor agonists, sodium liothyronine, sodiumlevothyroxine, KB-2611 or the like are illustrated; as cholesterolabsorption inhibitors, ezetimibe, SCH-48461 or the like are illustrated;as lipase inhibitors, orlistat, ATL-962, AZM-131, RED-103004 or the likeare illustrated; as carnitine palmitoyltransferase inhibitors, etomoxiror the like are illustrated; as squalene synthase inhibitors,SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393,ER-27856 or the like are illustrated; as nicotinic acid derivatives,nicotinic acid, nicotinamide, nicomol, niceritrol, acipimox, nicorandilor the like are illustrated; as bile acid sequestrants, colestyramine,colestilan, colesevelam hydrochloride, GT-102-279 or the like areillustrated; as sodium/bile acid cotransporter inhibitors, 264W94,S-8921, SD-5613 or the like are illustrated; and as cholesterol estertransfer protein inhibitors, PNU-107368E, SC-795, JTT-705, CP-529414 orthe like are illustrated. These drugs, probcol, microsomal trigylceridetransfer protein inhibitors, lipoxygenase inhibitors and low-densitylipoprotein receptor enhancers are preferably used for hyperlipidemia,hypercholesterolemia, hypertrigly-ceridemia or lipid metabolismdisorder.

As appetite suppressants, monoamine reuptake inhibitors, serotoninreuptake inhibitors, serotonin releasing stimulants, serotonin agonists(especially 5HT_(2C)-agonists), noradrenaline reuptake inhibitors,noradrenaline releasing stimulants, α₁-adrenoceptor agonists,β₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptorantagonists, γ-aminobutyric acid receptor antagonists, H₃-histamineantagonists, L-histidine, leptin, leptin analogues, leptin receptoragonists, melanocortin receptor agonists (especially, MC3-R agonists,MC4-Ragonists), α-melanocyte stimulating hormone, cocaine- andamphetamine-regulated transcript, mahogany protein, enterostatinagonists, calcitonin, calcitonin-gene-related peptide, bombesin,cholecystokinin agonists (especially CCK-A agonists),corticotropin-releasing hormone, corticotrophin-releasing hormoneanalogues, corticotropin-releasing hormone agonists, urocortin,somatostatin, somatostatin analogues, somatostatin receptor agonists,pituitary adenylate cyclase-activating peptide, brain-derivedneurotrophic factor, ciliary neurotrophic factor, thyrotropin-releasinghormone, neurotensin, sauvagine, neuropeptide Y antagonists, opioidpeptide antagonists, galanin antagonists, melanin-concentrating hormoneantagonists, agouti-related protein inhibitors and orexin receptorantagonists are illustrated. Concretely, as monoamine reuptakeinhibitors, mazindol or the like are illustrated; as serotonin reuptakeinhibitors, dexfenfluramine hydrochloride, fenfluramine, sibutraminehydrochloride, fluvoxamine maleate, sertraline hydrochloride or the likeare illustrated; as serotonin agonists, inotriptan, (+)-norfenfluramineor the like are illustrated; as noradrenaline reuptake inhibitors,bupropion, GW-320659 or the like are illustrated; as noradrenalinereleasing stimulants, rolipram, YM-992 or the like are illustrated; asβ₂-adrenoceptor agonists, amphetamine, dextroamphetamine, phentermine,benzphetamine, methamphetamine, phendimetrazine, phenmetrazine,diethylpropion, phenylpropanolamine, clobenzorex or the like areillustrated; as dopamine agonists, ER-230, doprexin, bromocriptinemesylate or the like are illustrated; as cannabinoid receptorantagonists, rimonabant or the like are illustrated; as γ-aminobutyricacid receptor antagonists, topiramate or the like are illustrated; asH₃-histamine antagonists, GT-2394 or the like are illustrated; asleptin, leptin analogues or leptin receptor agonists, LY-355101 or thelike are illustrated; as cholecystokinin agonists (especially CCK-Aagonists), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849,GI-248573, GW-7178, GI-181771, GW-7854, A-71378 or the like areillustrated; and as neuropeptide Y antagonists, SR-120819-A, PD-160170,NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01,J-115814 or the like are illustrated. Appetite suppressants are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,hypertension, congestive heart failure, edema, hyperuricemia or gout,and more preferably for obesity because of stimulating or inhibiting theactivities of intracerebral monoamines or bioactive peptides in centralappetite regulatory system and suppressing the appetite, leading toreduction of energy intake.

As angiotensin-converting enzyme inhibitors, captopril, enalaprimaleate, alacepril, delapril hydrochloride, ramipril, lisinopril,imidapril hydrochloride, benazepril hydrochloride, ceronaprilmonohydrate, cilazapril, sodium fosinopril, perindopril erbumine,calcium moveltipril, quinapril hydro-chloride, spirapril hydrochloride,temocapril hydrochloride, trandolapril, calcium zofenopril, moexiprilhydrochloride, rentiapril or the like are illustrated.Angiotensin-converting enzyme inhibitors are preferably used fordiabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240,fasidotril, sampatrilat, GW-660511X, mixanpril, SA-7060, E-4030,SLV-306, ecadotril or the like are illustrated. Neutral endopeptidaseinhibitors are preferably used for diabetic complications orhypertension.

As angiotensin II receptor antagonists, candesartan cilexetil,candesartan cilexetil/hydrochlorothiazide, potassium losartan,eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174,L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701 or the like are illustrated. Angiotensin II receptorantagonists are preferably used for diabetic complications orhypertension.

As endothelin-converting enzyme inhibitors, CGS-31447, CGS-35066,SM-19712 or the like are illustrated; as endothelin receptorantagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355,PD-180988, sodium sitaxsentan, BMS-193884, darusentan, TBC-3711,bosentan, sodium tezosentan, J-104132, YM-598, S-0139, SB-234551,RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940 orthe like are illustrated. These drugs are preferably used for diabeticcomplications or hypertension, and more preferably for hypertension.

As diuretic agents, chlorthalidone, metolazone, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, methyclothiazide, indapamide,tripamide, mefruside, azosemide, etacrynic acid, torasemide, piretanide,furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone,triamterene, aminophylline, cicletanine hydrochloride, LLU-α,PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin,acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan,conivaptan hydrochloride or the like are illustrated. Diuretic drugs arepreferably used for diabetic complications, hypertension, congestiveheart failure or edema, and more preferably for hypertension, congestiveheart failure or edema because of reducing blood pressure or improvingedema by increasing urinary excretion.

As calcium antagonists, aranidipine, efonidipine hydrochloride,nicardipine hydrochloride, barnidipine hydrochloride, benidipinehydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine,nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besilate,pranidipine, lercanidipine hydrochloride, isradipine, elgodipine,azelnidipine, lacidipine, vatanidipine hydrochloride, lemildipine,diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride,S-verapamil, fasudil hydrochloride, bepridil hydrochloride, gallopamilhydrochloride or the like are illustrated; as vasodilatingantihypertensive agents, indapamide, todralazine hydrochloride,hydralazine hydrochloride, cadralazine, budralazine or the like areillustrated; as sympathetic blocking agents, amosulalol hydrochloride,terazosin hydrochloride, bunazosin hydrochloride, prazosinhydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol,metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride,nebivolol, betaxolol hydrochloride, pindolol, tertatolol hydrochloride,bevantolol hydrochloride, timolol maleate, carteolol hydrochloride,bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutololsulfate, acebutolol hydrochloride, tilisolol hydrochloride, nadolol,urapidil, indoramin or the like are illustrated; as centrally actingantihypertensive agents, reserpine or the like are illustrated; and asα₂-adrenoceptor agonists, clonidine hydrochloride, methyldopa, CHF-1035,guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine,talipexole hydrochloride or the like are illustrated. These drugs arepreferably used for hypertension.

As antiplatelets agents, ticlopidine hydrochloride, dipyridamole,cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazepdihydrochloride, trapidil, beraprost sodium, aspirin or the like areillustrated. Antiplatelets agents are preferably used foratherosclerosis or congestive heart failure.

As uric acid synthesis inhibitors, allopurinol, oxypurinol or the likeare illustrated; as uricosuric agents, benzbromarone, probenecid or thelike are illustrated; and as urinary alkalinizers, sodium hydrogencarbonate, potassium citrate, sodium citrate or the like areillustrated. These drugs are preferably used for hyperuricemia or gout.

In case of uses in combination with drugs other than SGLT2 inhibitors,for example, in the use for diabetes, the combination with at least onemember of the group consisting of an insulin sensitivity enhancer, aglucose absorption inhibitor, a biguanide, an insulin secretionenhancer, a SGLT2 inhibitors, an insulin or insulin analogue, a glucagonreceptor antagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist and an appetitesuppressant is preferable; the combination with at least one member ofthe group consisting of an insulin sensitivity enhancer, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitors, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogueand an amylin agonist is more preferable; and the combination with atleast one member of the group consisting of an insulin sensitivityenhancer, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitorand an insulin or insulin analogue is most preferable. Similarly, in theuse for diabetic complications, the combination with at least one memberof the group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer, aSGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, glycogen synthase kinase-3 inhibitors, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation endproducts formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acidantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptorantagonist, an endothelin-converting enzyme inhibitor, an endothelinreceptor antagonist and a diuretic agnet is preferable; and thecombination with at least one member of the group consisting of analdose reductase inhibitor, an angiotensin-converting enzyme inhibitor,a neutral endopeptidase inhibitor and an angiotensin II receptorantagonist is more preferable. Furthermore, in the use for obesity, thecombination with at least one member of the group consisting of aninsulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, a β₃-adrenoceptor agonist and an appetite suppressantis preferable; and the combination with at least one member of the groupconsisting of a SGLT2 inhibitor, a β₃-adrenoceptor agonist and anappetite suppressant is more preferable.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry sirups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered. Thepharmaceutical compositions of the present invention also includesustained release formulation including gastrointestinal mucoadhesiveformulation (e.g., International publications Nos. WO99/10010,WO99/26606, and Japanese patent publication No. 2001-2567).

These pharmaceutical compositions can be prepared by admixing with or bydiluting and dissolving with an appropriate pharmaceutical additive suchas excipients, disintegrators, binders, lubricants, diluents, buffers,isotonicities, antiseptics, moistening agents, emulsifiers, dispersingagents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with conventional methods. In caseof the uses of the compound of the present invention in combination withthe drug(s) other than SGLT1 inhibitors, they can be prepared byformulating each active ingredient together or individually.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compoundrepresented by the above general formula (I), a pharmaceuticallyacceptable salt thereof or a prodrug thereof as the active ingredient isappropriately decided depending on the age, sex, body weight and degreeof symptoms and treatment of each patient, which is approximately withinthe range of from 0.1 to 1,000 mg per day per adult human in the case oforal administration and approximately within the range of from 0.01 to300 mg per day per adult human in the case of parenteral administration,and the daily dose can be divided into one to several doses per day andadministered suitably. Also, in case of the uses of the compound of thepresent invention in combination with the drug(s) other than SGLT1inhibitors, the dosage of the compound of the present invention can bedecreased, depending on the dosage of the drug(s) other than SGLT1inhibitors.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

Reference Example 1 2-Amino-2-methylpropionamide

To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (1 g)in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (0.63g), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (1.21g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2 mL), andthe mixture was stirred at room temperature overnight. The reactionmixture was poured into water, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with 0.5 mol/Lhydrochloric acid, water, 1 mol/L aqueous sodium hydroxide solution,water and brine successively, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure to give2-benzyloxycarbonylamino-2-methylpropionamide (0.26 g). This materialwas dissolved in methanol (5 mL). To the solution was added 10%palladium-carbon powder (30 mg), and the mixture was stirred under ahydrogen atmosphere for 3 hours. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure togive the title compound (0.11 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, s), 1.9 (2H, brs), 6.83 (1H, brs),7.26 (1H, brs)

Reference Example 24-[(4-Bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a suspension of sodium hydride (60%, 3.85 g) in tetrahydrofuran (250mL) was added ethyl 4-methyl-3-oxo-pentanoate (15.2 g), and the mixturewas stirred at 0° C. for 10 minutes. To the reaction mixture was added asolution of 4-bromobenzyl bromide (20 g) in tetrahydrofuran (100 mL),and the mixture was stirred at room temperature overnight. To thereaction mixture was added water, and the resulting mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and the solvent was removed under reduced pressure. To asolution of the residue in toluene (10 mL) was added hydrazinemonohydrate (8.01 g), and the mixture was stirred at 100° C. overnight.After cooling the reaction mixture to room temperature, the solvent wasremoved under reduced pressure. To the residue was added ethyl acetate(20 mL), and the mixture was stirred at room temperature for 2 hours.The precipitated crystals were collected by filtration. The collectedcrystals were washed with water and n-hexane successively, and dried at40° C. under reduced pressure to give the title compound (11.5 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.07 (6H, d, J=7.1 Hz), 2.75-2.9 (1H, m), 3.55(2H, s), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m)

Reference Example 33-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole

To a suspension of4-[(4-bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (5.0g) in dichloro-methane (50 mL) were added acetobromo-α-D-glucose (7.0g), benzyltri(n-butyl)ammonium chloride (5.3 g) and 5 mol/L aqueoussodium hydroxide solution (8.5 mL), and the mixture was stirred at roomtemperature overnight. The organic layer was separated, and the solventwas removed under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) togive the title compound (4.12 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.25 (6H, m), 1.86 (3H, s), 2.01 (3H, s), 2.03(3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.58 (1H, d, J=16.2 Hz), 3.64(1H, d, J=16.2 Hz), 3.8-3.95 (1H, m), 4.15 (1H, dd, J=12.4 Hz, 2.2 Hz),4.32 (1H, dd, J=12.4 Hz, 3.9 Hz), 5.15-5.35 (3H, m), 5.53 (1H, d, J=7.5Hz), 6.95-7.05 (2H, m), 7.3-7.4 (2H, m)

Reference Example 43-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole(3.0 g) and 3-butenoic acid (1.0 g) in acetonitrile (15 mL) were addedtriethylamine (2.4 g), palladium acetate (II) (0.11 g) andtris(2-methylphenyl)phosphine (0.29 g), and the mixture was refluxedovernight under shading the light. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to givethe title compound (1.74 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.84 (3H, s), 2.01 (3H, s), 2.02(3H, s), 2.05 (3H, s), 2.8-2.95 (1H, m), 3.2-3.3 (2H, m), 3.59 (1H, d,J=16.0 Hz), 3.66 (1H, d, J=16.0 Hz), 3.8-3.9 (1H, m), 4.18 (1H, dd,J=12.3 Hz, 1.8 Hz), 4.33 (1H, dd, J=12.3 Hz, 3.8 Hz), 5.15-5.35 (3H, m),5.4-5.5 (1H, m), 6.2-6.3 (1H, m), 6.4-6.5 (1H, m), 7.0-7.1 (2H, m),7.2-7.3 (2H, m)

Reference Example 53-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 4 using acrylic acid instead of 3-butenoic acid.

¹H-NMR (CDCl₃) δ ppm: 1.19 (6H, d, J=7.3 Hz), 1.84 (3H, s), 2.01 (3H,s), 2.04 (3H, s), 2.05 (3H, s), 2.85-3.0 (1H, m), 3.66 (1H, d, J=16.2Hz), 3.73 (1H, d, J=16.2 Hz), 3.85-3.95 (1H, m), 4.2 (1H, dd, J=12.6 Hz,2.2 Hz), 4.34 (1H, dd, J=12.6 Hz, 4.1 Hz), 5.15-5.35 (3H, m), 5.5 (1H,d, J=7.7 Hz), 6.4 (1H, d, J=15.7 Hz), 7.15-7.2 (2H, m), 7.4-7.5 (2H, m),7.71 (1H, d, J=15.7 Hz)

Example 14-({4-[3-(Carbamoylmethylcarbamoyl)propyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole(0.34 g) in N,N-dimethyl-formamide (1 mL) were added glycinamidehydrochloride (0.12 g), 1-hydroxybenzotriazole (0.09 g),1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.15 g)and triethylamine (0.27 g), and the mixture was stirred at roomtemperature overnight. The insoluble material was removed by filtration.To the filtrate was added 5 mol/L aqueous sodium hydroxide solution (0.5mL), and the mixture was stirred at room temperature for 1 hour. Theinsoluble material was removed by filtration, and the filtrate waspurified by preparative reverse phase column chromatography (ShiseidoCAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minutelinear gradient, water/acetonitrile=90/10-10/90) to give4-({4-[(1E)-3-(carbamoyl-methylcarbamoyl)prop-1-enyl]phenyl}methyl)-3-(β-D-gluco-pyranosyloxy)-5-isopropyl-1H-pyrazole(0.03 g). This material was dissolved in methanol (1 mL). To thesolution was added 10% palladium-carbon powder (0.01 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 3 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(0.02 g).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.85-1.95 (2H, m), 2.25 (2H, t,J=7.6 Hz), 2.6 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.25-3.4 (4H, m),3.6-3.9 (6H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 24-{[4-(3-Carbamoylpropyl)phenyl]methyl}-3-(β-D-gluco-pyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using ammonium chloride instead of glycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.8-1.95 (2H, m), 2.19 (2H, t,J=7.6 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.3-3.45 (4H, m),3.6-3.8 (3H, m), 3.8-3.9 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 34-({4-[3-(2-Carbamoylethylcarbamoyl)propyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 3-aminopropionamide instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.8-1.95 (2H, m), 2.15 (2H, t,J=7.3 Hz), 2.4 (2H, t, J=6.7 Hz), 2.56 (2H, t, J=7.5 Hz), 2.85-2.95 (1H,m), 3.25-3.45 (6H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H,m)

Example 44-({4-[3-(2-Aminoethylcarbamoyl)propyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N-benzyloxycarbonyl-1,2-diaminoethane hydrochlorideinstead of glycinamide hydro-chloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.85-1.95 (2H, m), 2.19 (2H, t,J=7.6 Hz), 2.58 (2H, t, J=7.5 Hz), 2.8 (2H, t, J=6.1 Hz), 2.85-2.95 (1H,m), 3.2-3.4 (6H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 54-({4-[3-(3-Aminopropylcarbamoyl)propyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N-benzyloxycarbonyl-1,3-diaminopropane hydrochlorideinstead of glycinamide hydro-chloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.6-1.7 (2H, m), 1.8-1.95 (2H,m), 2.17 (2H, t, J=7.7 Hz), 2.57 (2H, t, J=7.5 Hz), 2.68 (2H, t, J=7.1Hz), 2.85-2.95 (1H, m), 3.22 (2H, t, J=6.7 Hz), 3.25-3.45 (4H, m),3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 64-({4-[3-(4-Aminobutylcarbamoyl)propyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N-benzyloxycarbonyl-1,4-diaminobutane hydrochlorideinstead of glycinamide hydro-chloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.45-1.65 (4H, m), 1.8-1.95 (2H,m), 2.16 (2H, t, J=7.5 Hz), 2.57 (2H, t, J=7.7 Hz), 2.83 (2H, t, J=7.0Hz), 2.85-3.0 (1H, m), 3.17 (2H, t, J=6.6 Hz), 3.25-3.45 (4H, m),3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 74-[(4-{3-[(S)-1-Carbamoyl-2-(4-hydroxyphenyl)ethyl-carbamoyl]propyl}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using L-tyrosine amide hydrochloride instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.7-1.8 (2H, m), 2.1-2.2 (2H, m),2.44 (2H, t, J=7.5 Hz), 2.76 (1H, dd, J=13.9 Hz, 9.3 Hz), 2.85-2.95 (1H,m), 3.04 (1H, dd, J=13.9 Hz, 5.5 Hz), 3.25-3.45 (4H, m), 3.6-3.9 (4H,m), 4.57 (1H, dd, J=9.3 Hz, 5.5 Hz), 5.0-5.1 (1H, m), 6.65-6.75 (2H, m),6.95-7.15 (6H, m)

Example 84-{[4-(3-Benzylcarbamoylpropyl)phenyl]methyl}-3-(β-D-gluco-pyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using benzylamine instead of glycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-1.95 (2H, m), 2.22 (2H, t,J=7.5 Hz), 2.57 (2H, t, J=7.5 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m),3.6-3.9 (4H, m), 4.33 (2H, s), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m),7.15-7.45 (5H, m)

Example 93-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-phenethyl-carbamoylpropyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using phenethylamine instead of glycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.75-1.9 (2H, m), 2.12 (2H, t,J=7.5 Hz), 2.51 (2H, t, J=7.7 Hz), 2.77 (2H, t, J=7.5 Hz), 2.8-2.95 (1H,m), 3.25-3.45 (6H, m), 3.6-3.9 (4H, m), 5.0-5.15 (1H, m), 6.95-7.05 (2H,m), 7.05-7.3 (7H, m)

Example 103-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[3-(3-pyridyl-methylcarbamoyl)propyl]phenyl}methyl)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 3-picolylamine instead of glycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.85-1.95 (2H, m), 2.22 (2H, t,J=7.6 Hz), 2.56 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m),3.6-3.9 (4H, m), 4.37 (2H, s), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m),7.35-7.45 (1H, m), 7.7-7.8 (1H, m), 8.4-8.45 (1H, m), 8.45-8.5 (1H, m)

Example 113-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(2-pyridyl)ethylcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 2-(2-aminoethyl)pyridine instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.75-1.9 (2H, m), 2.11 (2H, t,J=7.5 Hz), 2.51 (2H, t, J=7.6 Hz), 2.85-3.0 (3H, m), 3.25-3.45 (4H, m),3.52 (2H, t, J=6.9 Hz), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 6.95-7.15 (4H,m), 7.2-7.35 (2H, m), 7.7-7.8 (1H, m), 8.4-8.5 (1H, m)

Example 123-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(di-methylamino)ethylcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N,N-dimethylethylenediamine instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.8-1.95 (2H, m), 2.17 (2H, t,J=7.6 Hz), 2.25 (6H, s), 2.42 (2H, t, J=6.9 Hz), 2.57 (2H, t, J=7.5 Hz),2.85-2.95 (1H, m), 3.25-3.4 (6H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m),7.0-7.15 (4H, m)

Example 133-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(morpholin-4-yl)ethylcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 4-(2-aminoethyl)morpholine instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.8-1.95 (2H, m), 2.17 (2H, t,J=7.6 Hz), 2.4-2.55 (6H, m), 2.58 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m),3.25-3.45 (6H, m), 3.6-3.9 (8H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 143-(β-D-Glucopyranosyloxy)-4-{[4-(3-{2-[bis(2-hydroxyethyl)-amino]ethylcarbamoyl}propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N,N-bis(2-hydroxyethyl)-ethylenediamine instead ofglycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.8-1.95 (2H, m), 2.18 (2H, t,J=7.5 Hz), 2.5-2.7 (8H, m), 2.85-2.95 (1H, m), 3.25 (2H, t, J=6.4 Hz),3.3-3.4 (4H, m), 3.5-3.9 (8H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 153-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{3-[bis(2-hydroxyethyl)amino]propylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N,N-bis(2-hydroxyethyl)-1,3-diaminopropane instead ofglycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.6-1.75 (2H, m), 1.8-1.95 (2H,m), 2.17 (2H, t, J=7.5 Hz), 2.5-2.75 (8H, m), 2.8-2.95 (1H, m), 3.21(2H, t, J=6.7 Hz), 3.25-3.45 (4H, m), 3.5-3.9 (8H, m), 5.0-5.15 (1H, m),7.0-7.2 (4H, m)

Example 163-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[3-(di-methylamino)propylcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N,N-dimethyl-1,3-diamino-propane instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.6-1.75 (2H, m), 1.8-1.95 (2H,m), 2.16 (2H, t, J=7.5 Hz), 2.22 (6H, s), 2.3-2.35 (2H, m), 2.57 (2H, t,J=7.6 Hz), 2.85-2.95 (1H, m), 3.17 (2H, t, J=6.9 Hz), 3.25-3.45 (4H, m),3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 173-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-(imidazol-1-yl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 1-(2-aminoethyl)imidazole instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.8-2.0 (4H, m), 2.17 (2H, t,J=7.6 Hz), 2.57 (2H, t, J=7.7 Hz), 2.85-2.95 (1H, m), 3.14 (2H, t, J=6.8Hz), 3.3-3.45 (4H, m), 3.6-3.9 (4H, m), 4.03 (2H, t, J=7.0 Hz), 5.0-5.1(1H, m), 6.9-7.0 (1H, m), 7.0-7.15 (5H, m), 7.6-7.7 (1H, m)

Example 183-(β-D-Glucopyranosyloxy)-4-({4-[3-(2-hydroxyethyl)-carbamoylpropyl]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 2-aminoethanol instead of glycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.8-1.95 (2H, m), 2.18 (2H, t,J=7.5 Hz), 2.57 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.27 (2H, t, J=5.8Hz), 3.3-3.5 (4H, m), 3.57 (2H, t, J=5.9 Hz), 3.6-3.9 (4H, m), 5.0-5.1(1H, m), 7.0-7.15 (4H, m)

Example 193-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-(hydroxy-methyl)ethyl]carbamoylpropyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 2-amino-1,3-propanediol instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.8-1.95 (2H, m), 2.21 (2H, t,J=7.6 Hz), 2.58 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.3-3.45 (4H, m),3.55-3.95 (9H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 203-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-hydroxy-methyl-1-(methyl)ethyl]carbamoylpropyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 2-amino-2-methyl-1,3-propanediol instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.22 (3H, s), 1.8-1.95 (2H, m),2.19 (2H, t, J=7.7 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.55-3.9 (8H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 213-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using tris(hydroxymethyl)amino-methane instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.8-1.95 (2H, m), 2.23 (2H, t,J=7.5 Hz), 2.59 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m),3.6-3.9 (10H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 224-[(4-{3-[(S)-1-(Carbamoyl)ethylcarbamoyl]propyl}phenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using L-alanine amide hydrochloride instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.32 (3H, d, J=7.2 Hz), 1.8-1.95(2H, m), 2.15-2.25 (2H, m), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 4.32 (1H, q, J=7.2 Hz), 5.0-5.1 (1H,m), 7.0-7.15 (4H, m)

Example 234-[(4-{3-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]propyl}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using L-serine amide hydrochloride instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-1.95 (2H, m), 2.2-2.3 (2H,m), 2.59 (2H, t, J=7.4 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m),3.6-3.9 (6H, m), 4.4 (1H, t, J=5.2 Hz), 5.0-5.1 (1H, m), 7.05-7.15 (4H,m)

Example 244-[(4-{3-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]propyl}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using 2-amino-2-methylpropionamide instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.44 (6H, s), 1.8-1.95 (2H, m),2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.4 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 254-[(4-{3-[2-(Acetylamino)ethylcarbamoyl]propyl}phenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using N-acetylethylenediamine instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.8-1.95 (5H, m), 2.16 (2H, t,J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.2-3.45 (8H, m),3.6-3.9 (4H, m), 5.0-5.15 (1H, m), 7.0-7.15 (4H, m)

Example 264-({4-[(1E)-3-Carbamoylprop-1-enyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole(32 mg) in N,N-dimethyl-formamide (1 mL) were added ammonium chloride (8mg), 1-hydroxybenzotriazole (9 mg),1-ethyl-3-(3-dimethylamino-propyl)carbodiimidehydrochloride (15 mg) andtriethylamine (21 mg), and the mixture was stirred at room temperatureovernight. The insoluble material was removed by filtration, 5 mol/Laqueous sodium hydroxide solution (0.5 mL) was added to the filtrate,and the resulting mixture was stirred at room temperature for 1 hour.The insoluble material was removed by filtration, and the filtrate waspurified by preparative reverse phase column chromatography (ShiseidoCAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minutelinear gradient, water/acetonitrile=90/10-10/90) to give the titlecompound (7 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 2.8-2.95 (1H, m), 3.05-3.15 (2H,m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.15 (1H, m), 6.15-6.35 (1H,m), 6.48 (1H, d, J=15.6 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (2H, m)

Example 273-(β-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[2-hydroxy-1-hydroxymethyl-1-(methyl)ethylcarbamoyl]vinyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using 2-amino-2-methyl-1,3-propanediol and3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of ammonium chloride and3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole,respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.3 (3H, s), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.6-3.9 (8H, m), 5.05-5.15 (1H, m), 6.64 (1H, d,J=15.9 Hz), 7.2-7.3 (2H, m), 7.4-7.5 (3H, m)

Example 283-(β-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using tris(hydroxymethyl)-aminomethane and3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of ammonium chloride and3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole,respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 2.85-2.95 (1H, m), 3.25-3.45(4H, m), 3.67 (1H, dd, J=12.1 Hz, 5.3 Hz), 3.7-3.9 (9H, m), 5.05-5.15(1H, m), 6.69 (1H, d, J=15.7 Hz), 7.24 (2H, d, J=8.3 Hz), 7.45 (2H, d,J=8.3 Hz), 7.48 (1H, d, J=15.7 Hz)

Example 294-[(4-{(1E)-2-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]vinyl}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using 2-amino-2-methylpropionamide and3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of ammonium chloride and3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole,respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.52 (6H, s), 2.85-2.95 (1H,m), 3.25-3.45 (4H, m), 3.67 (1H, dd, J=11.9 Hz, 5.1 Hz), 3.7-3.9 (3H,m), 5.0-5.15 (1H, m), 6.6 (1H, d, J=15.8 Hz), 7.24 (2H, d, J=8.4 Hz),7.4-7.5 (3H, m)

Example 303-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethyl-carbamoyl)-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (0.5g) in dichloromethane (5 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g),1-hydroxybenzotriazole (0.43 g) and 2-aminoethanol (1.16 g), and themixture was stirred at room temperature overnight. To the reactionmixture was added water, and the resulting mixture was extracted withdichloromethane. The organic layer was washed with a saturated aqueoussodium hydrogen carbonate solution and brine successively, and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was dissolved in methanol (5 mL). To thesolution was added 10% palladium-carbon powder (0.10 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 4 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give2-(2-amino-2-methylpropionyl-amino)ethanol (0.11 g). To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole(70 mg) in N,N-dimethylformamide (0.5 mL) were added1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride (32 mg),1-hydroxybenzotriazole (23 mg) and2-(2-amino-2-methyl-propionylamino)ethanol (0.11 g), and the mixture wasstirred at room temperature overnight. The insoluble material wasremoved by filtration, 5 mol/L aqueous sodium hydroxide solution (0.25mL) was added to the filtrate, and the resulting mixture was stirred atroom temperature for 1 hour. To the mixture was added acetic acid (0.09mL), and the mixture was diluted with water (1 mL). The insolublematerial was removed by filtration, and the filtrate was purified bypreparative reverse phase column chromatography (Shiseido CAPCELL PAKUG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute lineargradient, water/methanol=90/10-10/90) to give3-(β-D-glucopyranosyloxy)-4-(4-{(1E)-3-[1-(2-hydroxyethylcarbamoyl)-1-methylethylcarbamoyl]prop-1-enyl}phenyl)methyl)-5-isopropyl-1H-pyrazole(14 mg). This material was dissolved in methanol (0.5 mL). To thesolution was added 10% palladium-carbon powder (7 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 2 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(11 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.19 (2H, t, J=7.6 Hz), 2.58 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m),3.25-3.45 (6H, m), 3.56 (2H, t, J=5.8 Hz), 3.6-3.9 (4H, m), 5.0-5.1 (1H,m), 7.0-7.15 (4H, m)

Example 314-[(4-{3-[1-Carbamoylmethylcarbamoyl-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 30 using glycinamide hydrochloride and triethylamine instead of2-aminoethanol.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.22 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.7 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.6-3.9 (6H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Reference Example 63-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 3 using acetobromo-α-D-galactose instead ofacetobromo-α-D-glucose.

¹H-NMR (CDCl₃) δ ppm: 1.17 (6H, d, J=7.3 Hz), 1.88 (3H, s), 1.99 (3H,s), 2.02 (3H, s), 2.17 (3H, s), 2.8-2.95 (1H, m), 3.59 (1H, d, J=16.0Hz), 3.66 (1H, d, J=16.0 Hz), 4.05-4.25 (3H, m), 5.1 (1H, dd, J=10.4 Hz,3.5 Hz), 5.35-5.45 (2H, m), 5.57 (1H, d, J=8.2 Hz), 6.95-7.05 (2H, m),7.3-7.4 (2H, m)

Reference Example 73-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 4 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-bromophenyl)-methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.83 (3H, s), 1.99 (3H, s), 2.00(3H, s), 2.17 (3H, s), 2.8-2.95 (1H, m), 3.26 (2H, d, J=6.9 Hz), 3.6(1H, d, J=16.2 Hz), 3.69 (1H, d, J=16.2 Hz), 4.05-4.3 (3H, m), 5.1 (1H,dd, J=10.1 Hz, 3.5 Hz), 5.3-5.5 (3H, m), 6.2-6.3 (1H, m), 6.45 (1H, d,J=15.9 Hz), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m), 10.0-12.0 (1H, br)

Example 323-(β-D-Galactopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-hydroxy-methyl-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.22 (3H, s), 1.8-1.95 (2H, m),2.19 (2H, t, J=7.4 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.52(1H, dd, J=9.8 Hz, 3.6 Hz), 3.55-3.8 (10H, m), 3.85-3.9 (1H, m),5.05-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 334-[(4-{3-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]propyl}-phenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.44 (6H, s), 1.8-1.95 (2H, m),2.19 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.52(1H, dd, J=9.7 Hz, 3.4 Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m),3.85-3.9 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 344-({4-[3-(2-Aminoethylsulfamoyl)propyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

A suspension of sodium allylsulfonate (2.0 g) in thionyl chloride (10.4mL) was heated at 70° C. and stirred for 1.5 days. The insolublematerial was removed by filtration, and the solvent of the filtrate wasremoved under reduced pressure. The obtained residue was dissolved indry tetrahydrofuran (10 mL), and the solvent was removed under reducedpressure. The obtained residue was again dissolved in drytetrahydrofuran (10 mL), and the solvent was removed under reducedpressure to give allylsulfonyl chloride (1.26 g). To a suspension ofN-benzyloxycarbonyl-1,2-diaminoethane hydrochloride (0.82 g) andtriethylamine (0.63 g) in dichloromethane (5 mL) was added allylsulfonylchloride (0.25 g) at room temperature, and the mixture was stirredovernight. The reaction was quenched by addition of water, and theorganic layer of the resulting mixture was separated. The organic layerwas washed with 1 mol/L hydrochloric acid, a saturated aqueous sodiumhydrogen carbonate solution and brine successively, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give N-(2-benzyloxycarbonylaminoethyl)allylsulfonamide (82 mg). Thismaterial was dissolved in acetonitrile (0.25 mL). To the solution wereadded3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole(70 mg), triethylamine (57 mg), palladiumacetate (II) (3 mg) andtris(2-methylphenyl)phosphine (7 mg), and the mixture was refluxedovernight under shading the light. The solvent was removed under reducedpressure, and the residue was dissolved in methanol (0.5 mL). To thissolution was added 5 mol/L aqueous sodium hydroxide solution (0.25 mL),and the mixture was stirred at room temperature for 1 hour. Theinsoluble material was removed by filtration, and the filtrate waspurified by preparative reverse phase column chromatography (ShiseidoCAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minutelinear gradient, water/methanol=90/10-10/90) to give4-({4-[(1E)-3-(2-benzyloxycarbonylaminoethylsulfamoyl)-prop-1-enyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(14 mg). This material was dissolved in methanol (0.5 mL). To thesolution was added 10% palladium-carbon powder (5 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 3 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(10 mg).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 2.0-2.1 (2H, m), 2.65-2.75 (4H,m), 2.85-2.95 (1H, m), 2.95-3.05 (4H, m), 3.25-3.45 (4H, m), 3.6-3.9(4H, m), 5.0-5.1 (1H, m), 7.05-7.2 (4H, m)

Example 354-[(4-{3-[1-Carbamoyl-1-(methyl)ethylsulfamoyl]propyl}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a suspension of benzyl 2-amino-2-methylpropionate p-toluenesulfonicacid salt (Tetrahedron, 1991, Vol. 47, No. 2, pp. 259-270; 3.9 g) andtriethylamine (2.7 g) in dichloromethane (15 mL) was added allylsulfonylchloride (0.75 g) at room temperature, and the mixture was stirredovernight. The reaction was quenched by addition of water, and theorganic layer of the resulting mixture was separated. The organic layerwas washed with 1 mol/L hydrochloric acid, a saturated aqueous sodiumhydrogen carbonate solution and brine successively, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give N-[1-benzyloxycarbonyl-1-(methyl)-ethyl]allylsulfonamide (0.48g). To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)-methyl]-5-isopropyl-1H-pyrazole(0.40 g), N-[1-benzyloxy-carbonyl-1-(methyl)ethyl]allylsulfonamide (0.48g) in acetonitrile (1 mL) were added triethylamine (0.32 g), palladiumacetate (II) (14 mg) and tris(2-methylphenyl)phosphine (39 mg), and themixture was refluxed overnight under shading the light. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethylacetate) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[1-benzyloxycarbonyl-1-(methyl)ethylsulfamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(0.11 g). This material was dissolved in methanol (1 mL). To thesolution was added 10% palladium-carbon powder (50 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 2 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylsulfamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(95 mg). To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylsulfamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(50 mg) in N,N-dimethylformamide (0.5 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg) and1-hydroxybenzotriazole (13 mg). An ammonia gas was bubbled into themixture for about 2 minutes, and the resulting mixture was stirred atroom temperature overnight. The insoluble material was removed byfiltration. To the filtrate was added 5 mol/L aqueous sodium hydroxidesolution (0.25 mL), and the mixture was stirred at room temperature for1 hour. To the reaction mixture was added acetic acid (0.09 mL), and themixture was diluted with water (1 mL). The insoluble material wasremoved by filtration, and the filtrate was purified by preparativereverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient,water/methanol=90/10-10/90) to give the title compound (14 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.43 (6H, s), 2.0-2.15 (2H, m),2.7 (2H, t, J=7.4 Hz), 2.8-2.95 (1H, m), 2.95-3.1 (2H, m), 3.25-3.45(4H, m), 3.6-3.9 (4H, m), 5.0-5.15 (1H, m), 7.05-7.2 (4H, m)

Reference Example 8 Benzyl Hydroxypivalate

To a suspension of hydroxypivalic acid (3 g) and potassium carbonate(3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl bromide (2.9mL), and the mixture was stirred at room temperature for 5 hours. Thereaction mixture was poured into water, and the resulting mixture wasextracted with diethyl ether. The organic layer was washed with watertwice and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give the title compound (4.7 g).

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, s), 2.33 (1H, t, J=6.7 Hz), 3.58 (2H, d,J=6.7 Hz), 5.15 (2H, s), 7.3-7.4 (5H, m)

Reference Example 9 4-(2-Benzyloxycarbonyl-2-methylpropoxy)benzaldehyde

To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl hydroxypivalate(4.7 g) and triphenylphosphine (6.4 g) in tetrahydrofuran (22 mL) wasadded diethyl azodicarboxylate (40% toluene solution, 11 mL), and themixture was stirred at room temperature for 2 days. The reaction mixturewas poured into water, and the resulting mixture was extracted withdiethyl ether. The organic layer was washed with water and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give the titlecompound (0.97 g).

¹H-NMR (CDCl₃) δ ppm: 1.36 (6H, s), 4.07 (2H, s), 5.15 (2H, s), 6.9-7.0(2H, m), 7.2-7.35 (5H, m), 7.75-7.85 (2H, m), 9.89 (1H, s)

Reference Example 10[4-(2-Benzyloxycarbonyl-2-methylpropoxy)phenyl]methanol

To a solution of 4-(2-benzyloxycarbonyl-2-methyl-propoxy)benzaldehyde(0.97 g) in tetrahydrofuran (20 mL) was added sodium borohydride (59mg), and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was poured into 0.5 mol/L hydrochloric acid, and theresulting mixture was extracted with diethyl ether. The organic layerwas washed with water and brine successively, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=6/1-3/2) to give the title compound (0.95 g).

¹H-NMR (CDCl₃) δ ppm: 1.34 (6H, s), 1.51 (1H, t, J=5.9 Hz), 3.99 (2H,s), 4.62 (2H, d, J=5.9 Hz), 5.15 (2H, s), 6.8-6.9 (2H, m), 7.25-7.35(7H, m)

Reference Example 114-{[4-(2-Benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of[4-(2-benzyloxycarbonyl-2-methyl-propoxy)phenyl]methanol (0.95 g) intetrahydrofuran (8 mL) were added triethylamine (0.48 mL) andmethansulfonyl chloride (0.26 mL) under ice-cooling, and the mixture wasstirred for 1 hour. The insoluble material was removed by filtration.The obtained solution of[4-(2-benzyloxycarbonyl-2-methylpropoxy)-phenyl]methyl mesylate intetrahydrofuran was added to a suspension of sodium hydride (60%, 139mg) and ethyl 4-methyl-3-oxopentanoate (0.52 g) in tetrahydrofuran (15mL), and the mixture was heated for reflux for 15 hours. To the reactionmixture was added 1 mol/L hydrochloric acid, and the resulting mixturewas extracted with diethylether. The organic layer was washed with waterand dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure. To a solution of the residue in ethanol (10 mL)was added hydrazine monohydrate (0.16 mL), and the mixture was stirredat room temperature for 2 days. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent:dichloromethane/methanol=30/1-20/1) to give the title compound (0.25 g).

¹H-NMR (CDCl₃) δ ppm: 1.15 (6H, d, J=6.9 Hz), 1.32 (6H, s), 2.85-2.95(1H, m), 3.66 (2H, s), 3.94 (2H, s), 5.13 (2H, s), 6.7-6.8 (2H, m),7.05-7.15 (2H, m), 7.2-7.35 (5H, m)

Reference Example 123-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-5-iso-propyl-1H-pyrazole

To a solution of4-{[4-(2-benzyloxycarbonyl-2-methyl-propoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one(0.25 g), acetobromo-α-D-glucose (0.48 g) andbenzyl-tri(n-butyl)ammonium chloride (0.18 g) in dichloromethane (5 mL)was added 5 mol/L aqueous sodium hydroxide solution (0.35 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was purified by column chromatography on aminopropylated silicagel (eluent: n-hexane/ethyl acetate=1/1-1/3) to give the title compound(0.28 g).

¹H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=7.1 Hz), 1.32 (6H, s), 1.86 (3H,s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.56(1H, d, J=16.0 Hz), 3.62 (1H, d, J=16.0 Hz), 3.8-3.9 (1H, m), 3.92 (1H,d, J=8.7 Hz), 3.94 (1H, d, J=8.7 Hz), 4.15 (1H, dd, J=12.5 Hz, 2.4 Hz),4.31 (1H, dd, J=12.5 Hz, 4.2 Hz), 5.13 (2H, s), 5.15-5.3 (3H, m),5.55-5.65 (1H, m), 6.7-6.75 (2H, m), 6.95-7.05 (2H, m), 7.25-7.35 (5H,m)

Reference Example 133-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxy-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropy-1H-pyrazole(0.28 g) was dissolved in methanol (6 mL). To the solution was added 10%palladium-carbon powder (54 mg), and the mixture was stirred at roomtemperature under a hydrogen atmosphere overnight. The insolublematerial was removed by filtration, and the solvent of the filtrate wasremoved under reduced pressure to give the title compound (0.25 g).

¹H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=6.7 Hz), 1.33 (6H, s), 1.88 (3H,s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.85-3.0 (1H, m), 3.54(1H, d, J=15.8 Hz), 3.6 (1H, d, J=15.8 Hz), 3.8-3.9 (1H, m), 3.91 (1H,d, J=8.8 Hz), 3.93 (1H, d, J=8.8 Hz), 4.15 (1H, dd, J=12.5 Hz, 2.0 Hz),4.32 (1H, dd, J=12.5H, 4.0 Hz), 5.15-5.3 (3H, m), 5.4-5.45 (1H, m),6.7-6.8 (2H, m), 6.95-7.05 (2H, m)

Example 363-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(carbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)-methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxy-2-methylpropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole(0.13 g) in N,N-dimethyl-formamide (2 mL) were added L-alanine amidehydrochloride (46 mg), triethylamine (0.08 mL), 1-hydroxybenzotriazole(38 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.11 g), and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with water, asaturated aqueous sodium hydrogen carbonate solution, water and brinesuccessively, and dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent:dichloro-methane/methanol=20/1-10/1) to give the title compound (0.14g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.29 (3H, s), 1.32 (3H, s), 1.38(3H, d, J=7.5 Hz), 1.89 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H,s), 2.85-2.95 (1H, m), 3.57 (1H, d, J=16.0 Hz), 3.62 (1H, d, J=16.0 Hz),3.8-3.9 (2H, m), 3.94 (1H, d, J=9.1 Hz), 4.14 (1H, dd, J=12.5 Hz, 2.4Hz), 4.3 (1H, dd, J=12.5 Hz, 4.1 Hz), 4.4-4.55 (1H, m), 5.15-5.4 (4H,m), 5.58 (1H, d, J=8.0 Hz), 6.2-6.35 (1H, br), 6.67 (1H, d, J=7.3 Hz),6.7-6.8 (2H, m), 7.0-7.1 (2H, m)

Example 373-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di(methyl)ethylcarbamoyl]-2-methylpropoxy}-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 36 using 2-amino-2-methyl-1-propanol instead of L-alanine amidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.25 (6H, s), 1.27 (6H, s), 1.89(3H, s), 1.97 (3H, s), 2.01 (3H, s), 2.02 (3H, s), 2.85-3.0 (1H, m), 3.5(2H, s), 3.6 (2H, s), 3.89 (2H, s), 3.9-4.0 (1H, m), 4.11 (1H, dd,J=12.3 Hz, 2.2 Hz), 4.3 (1H, dd, J=12.3 Hz, 4.0 Hz), 5.05-5.15 (2H, m),5.25-5.35 (1H, m), 5.48 (1H, d, J=7.9 Hz), 6.75-6.9 (3H, m), 7.0-7.1(2H, m)

Example 383-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)ethylcarbamoyl]-2-methylpropoxy}-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 36 using 2-amino-2-methylpropionamide instead of L-alanine amidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.27 (6H, s), 1.49 (6H, s), 1.89(3H, s), 1.97 (3H, s), 2.01 (3H, s), 2.02 (3H, s), 2.85-3.0 (1H, m), 3.6(2H, s), 3.9-4.0 (3H, m), 4.11 (1H, dd, J=12.3 Hz, 2.4 Hz), 4.3 (1H, dd,J=12.3 Hz, 4.0 Hz), 5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48 (1H, d,J=8.4 Hz), 6.75-6.85 (2H, m), 7.0-7.1 (2H, m)

Example 394-[(4-{2-[(S)-1-(Carbamoyl)ethylcarbamoyl]-2-methyl-propoxy}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[(S)-1-(carbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole(0.14 g) in methanol (4 mL) was added sodium methoxide (28% methanolsolution, 0.04 mL), and the mixture was stirred at room temperature for1 hour. The reaction mixture was concentrated under reduced pressure,and the residue was purified by solid phase extraction on ODS (washingsolvent: distilled water, eluent: methanol) to give the title compound(94 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.29 (3H, s), 1.3 (3H, s), 1.35(3H, d, J=7.5 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.8 (3H, m),3.8-3.9 (1H, m), 3.94 (2H, s), 4.3-4.45 (1H, m), 5.0-5.1 (1H, m),6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 403-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-(dimethyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[(S)-1-(carbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.25 (6H, s), 1.27 (6H, s),2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5 (2H, s), 3.6-3.7 (2H, m), 3.74(1H, d, J=16.0 Hz), 3.8-3.95 (3H, m), 5.0-5.15 (1H, m), 6.75-6.9 (2H,m), 7.05-7.15 (2H, m)

Example 414-[(4-{2-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]-2-methyl-propoxy}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-iso-propyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[(S)-1-(carbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.27 (6H, s), 1.49 (6H, s),2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.8 (3H, m), 3.8-3.9 (1H, m),3.93 (2H, s), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 423-(β-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1-(hydroxymethyl)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 30 using 2-amino-1,3-propanediol instead of 2-aminoethanol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.43 (6H, s), 1.8-1.95 (2H, m),2.19 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.5-3.95 (9H, m), 5.0-5.15 (1H, m), 7.0-7.2 (4H, m)

Example 433-(β-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 30 using tris(hydroxymethyl)-aminomethane instead of2-aminoethanol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-3.0 (1H, m),3.25-3.45 (4H, m), 3.6-3.9 (10H, m), 5.0-5.15 (1H, m), 7.0-7.2 (4H, m)

Reference Example 14 4-Bromo-2-methylbenzyl alcohol

To a solution of 4-bromo-2-methylbenzoic acid (10 g) in tetrahydrofuran(60 mL) was added borane-dimethylsulfide complex (7.07 g) underice-cooling. The reaction mixture was stirred at room temperature for 5minutes, and stirred at 75° C. for 2 days. The reaction mixture wascooled to room temperature. A saturated aqueous potassium carbonatesolution was added to the reaction mixture, and the organic layer wasseparated. The organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure to give the title compound (9.0 g).

¹H-NMR (CDCl₃) δ ppm: 1.55-1.65 (1H, m), 2.36 (3H, s), 4.64 (2H, d,J=5.4 Hz), 7.2-7.25 (1H, m), 7.3-7.35 (2H, m)

Reference Example 154-[(4-Bromo-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) indichloromethane (50 mL) was added thionyl chloride (3.8 mL) underice-cooling, and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureto give 4-bromo-2-methylbenzyl chloride (9.8 g). To a suspension ofsodium hydride (60%, 2.1 g) in tetrahydrofuran (90 mL) was added ethyl4-methyl-3-oxo-pentanoate (7.5 g) under ice-cooling, and the reactionmixture was stirred at room temperature for 1 hour.4-Bromo-2-methyl-benzyl chloride (9.8 g) was added to the reactionmixture, and the resulting mixture was stirred at 70° C. for 3 days. Thereaction mixture was poured into a saturated aqueous ammonium chloridesolution, and the mixture was extracted with diethyl ether. The organiclayer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure. To asolution of the residue in toluene (20 mL) was added hydrazinemonohydrate (5.4 mL), and the mixture was stirred at 90° C. overnight.The reaction mixture was concentrated under reduced pressure, and theresidue was treated with n-hexane-diethyl ether (10/1) to crystallize.The crystals were collected by filtration and washed with n-hexane,water and n-hexane successively, and dried under reduced pressure togive the title compound (12.4 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.05 (6H, d, J=6.8 Hz), 2.28 (3H, s), 2.65-2.8(1H, m), 3.45 (2H, s), 6.82 (1H, d, J=8.2 Hz), 7.24 (1H, dd, J=8.2 Hz,1.8 Hz), 7.33 (1H, d, J=1.8 Hz), 8.5-12.0 (2H, br)

Reference Example 163-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 3 using4-[(4-bromo-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-[(4-bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.81 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.28 (3H, s), 2.75-2.9 (1H, m), 3.49 (1H, d,J=16.7 Hz), 3.59 (1H, d, J=16.7 Hz), 3.8-3.9 (1H, m), 4.05-4.2 (1H, m),4.3 (1H, dd, J=12.4 Hz, 4.0 Hz), 5.1-5.3 (3H, m), 5.5-5.6 (1H, m), 6.76(1H, d, J=8.2 Hz), 7.1-7.2 (1H, m), 7.25-7.3 (1H, m)

Reference Example 173-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 4 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.78 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.29 (3H, s), 2.75-2.9 (1H, m), 3.13 (2H, d,J=7.3 Hz), 3.54 (1H, d, J=16.8 Hz), 3.64 (1H, d, J=16.8 Hz), 3.8-3.9(1H, m), 4.05-4.15 (1H, m), 4.25-4.35 (1H, m), 5.1-5.3 (3H, m), 5.5-5.6(1H, m), 6.15-6.25 (1H, m), 6.46 (1H, d, J=16.1 Hz), 6.85 (1H, d, J=7.9Hz), 7.05 (1H, d, J=7.9 Hz), 7.15 (1H, s)

Reference Example 183-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 4 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand acrylic acid instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazoleand 3-butenoic acid, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.73 (3H, s), 1.99 (3H, s), 2.04(3H, s), 2.06 (3H, s), 2.35 (3H, s), 2.8-2.9 (1H, m), 3.58 (1H, d,J=17.2 Hz), 3.69 (1H, d, J=17.2 Hz), 3.85-3.95 (1H, m), 4.21 (1H, dd,J=12.4 Hz, 2.2 Hz), 4.35 (1H, dd, J=12.4 Hz, 3.9 Hz), 5.15-5.3 (3H, m),5.45 (1H, d, J=7.8 Hz), 6.4 (1H, d, J=15.8 Hz), 6.93 (1H, d, J=7.8 Hz),7.2-7.3 (1H, m), 7.3-7.4 (1H, m), 7.69 (1H, d, J=15.8 Hz)

Example 444-[(4-{3-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.44 (6H, s), 1.8-1.9 (2H, m),2.2 (2H, t, J=7.6 Hz), 2.3 (3H, S), 2.55 (2H, t, J=7.6 Hz), 2.75-2.9(1H, m), 3.2-3.4 (4H, m), 3.6-3.9 (4H, m), 4.95-5.1 (1H, m), 6.8-6.9(2H, m), 6.9-7.0 (1H, m)

Example 454-[(4-{(1E)-2-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]vinyl}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand ammonium chloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.52 (6H, s), 2.36 (3H, s),2.75-2.9 (1H, m), 3.2-3.4 (4H, m), 3.6-3.85 (4H, m), 5.0-5.1 (1H, m),6.58 (1H, d, J=15.8 Hz), 7.0 (1H, d, J=7.9 Hz), 7.2-7.3 (1H, m), 7.33(1H, s), 7.43 (1H, d, J=15.8 Hz)

Example 463-(β-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[2-hydroxy-1-hydroxymethyl-1-(methyl)ethylcarbamoyl]vinyl}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methyl-phenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand ammonium chloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.3 (3H, s), 2.36 (3H, s),2.75-2.9 (1H, m), 3.25-3.45 (4H, m), 3.6-3.85 (8H, m), 5.04 (1H, d,J=6.1 Hz), 6.62 (1H, d, J=15.5 Hz), 6.99 (1H, d, J=7.6 Hz), 7.26 (1H, d,J=7.6 Hz), 7.32 (1H, s), 7.42 (1H, d, J=15.5 Hz)

Example 473-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{(1E)-2-[2-(sulfamoylamino)ethylcarbamoyl]vinyl}-2-methylphenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleand N-sulfamoylethylenediamine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleand ammonium chloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 2.36 (3H, s), 2.75-2.9 (1H, m),3.19 (2H, t, J=6.3 Hz), 3.25-3.4 (4H, m), 3.47 (2H, t, J=6.3 Hz),3.6-3.7 (1H, m), 3.7-3.9 (3H, m), 5.04 (1H, d, J=7.3 Hz), 6.54 (1H, d,J=15.7 Hz), 7.0 (1H, d, J=7.9 Hz), 7.27 (1H, d, J=7.9 Hz), 7.33 (1H, s),7.47 (1H, d, J=15.7 Hz)

Reference Example 193-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole(0.4 g) in N,N-dimethyl-formamide (2 mL) were added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.18 g),1-hydroxybenzotriazole (0.13 g), benzyl 2-amino-2-methylpropionatep-toluenesulfonic acid salt (1.16 g) and triethylamine (0.64 g) at roomtemperature, and the mixture was stirred overnight. To the reactionmixture was added water, and the resulting mixture was extracted withdichloromethane. The organic layer was washed with water and brine, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate) to give3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{(1E)-3-[1-benzyloxy-carbonyl-1-(methyl)ethylcarbamoyl]prop-1-enyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(0.18 g). This material was dissolved in methanol (2 mL). To thesolution was added 10% palladium-carbon powder (50 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 4 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(0.15 g).

¹H-NMR (CDCl₃) δ ppm: 1.05-1.2 (6H, m), 1.57 (3H, s), 1.59 (3H, s), 1.85(3H, s), 1.85-1.95 (2H, m), 1.99 (3H, s), 2.02 (3H, s), 2.1-2.2 (5H, m),2.6 (2H, t, J=7.4 Hz), 2.8-2.95 (1H, m), 3.59 (1H, d, J=16.1 Hz), 3.68(1H, d, J=16.1 Hz), 4.0-4.1 (1H, m), 4.14 (1H, dd, J=11.0 Hz, 8.2 Hz),4.27 (1H, dd, J=11.0 Hz, 5.6 Hz), 5.08 (1H, dd, J=10.3 Hz, 3.5 Hz), 5.37(1H, d, J=8.1 Hz), 5.4-5.5 (2H, m), 6.19 (1H, s), 6.95-7.1 (4H, m)

Reference Example 203-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.2 (6H, m), 1.57 (3H, s), 1.58 (3H, s), 1.85(3H, s), 1.85-1.95 (2H, m), 2.0 (3H, s), 2.03 (3H, s), 2.05 (3H, s),2.15 (2H, t, J=7.6 Hz), 2.6 (2H, t, J=7.5 Hz), 2.8-2.95 (1H, m), 3.58(1H, d, J=15.7 Hz), 3.66 (1H, d, J=15.7 Hz), 3.8-3.9 (1H, m), 4.17 (1H,dd, J=11.9 Hz, 2.2 Hz), 4.34 (1H, dd, J=11.9 Hz, 3.4 Hz), 5.15-5.3 (3H,m), 5.35-5.45 (1H, m), 6.18 (1H, s), 6.95-7.1 (4H, m)

Reference Example 213-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-oxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.57 (3H, s), 1.58 (3H, s),1.76 (3H, s), 1.85-1.95 (2H, m), 1.99 (3H, s), 2.02 (3H, s), 2.05 (3H,s), 2.1-2.2 (2H, m), 2.25 (3H, s), 2.5-2.6 (2H, m), 2.7-2.85 (1H, m),3.51 (1H, d, J=16.8 Hz), 3.61 (1H, d, J=16.8 Hz), 3.8-3.9 (1H, m),4.1-4.2 (1H, m), 4.32 (1H, dd, J=12.2 Hz, 3.4 Hz), 5.15-5.3 (3H, m),5.38 (1H, d, J=8.1 Hz), 6.23 (1H, s), 6.77 (1H, d, J=7.8 Hz), 6.85 (1H,d, J=7.8 Hz), 6.93 (1H, s)

Example 483-(β-D-Galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(30 mg) in N,N-dimethylformamide (0.5 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg),1-hydroxybenzotriazole (9 mg) and 1-(2-hydroxyethyl)piperazine (54 mg),and the mixture was stirred at room temperature overnight. To thereaction mixture was added 5 mol/L aqueous sodium hydroxide solution(0.25 mL), and the resulting mixture was stirred at room temperature for1 hour. To the reaction mixture was added acetic acid (0.1 mL), and themixture was diluted with water (1 mL). The insoluble material wasremoved by filtration, and the filtrate was purified by preparativereverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient,water/acetonitrile=90/10-10/60) to give the title compound (4 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.17 (2H, t, J=7.7 Hz), 2.35-2.55 (6H, m), 2.58 (2H, t, J=7.6 Hz),2.8-2.95 (1H, m), 3.52 (1H, dd, J=9.7 Hz, 3.4 Hz), 3.55-3.8 (12H, m),3.87 (1H, d, J=3.4 Hz), 5.08 (1H, d, J=8.0 Hz), 7.0-7.15 (4H, m)

Example 493-(β-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1-(hydroxymethyl)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 2-amino-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.43 (6H, s), 1.8-1.95 (2H, m),2.19 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.5-3.95 (9H, m), 5.0-5.15 (1H, m), 7.0-7.2 (4H, m)

Example 503-(β-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand tris(hydroxymethyl)aminomethane instead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-3.0 (1H, m),3.25-3.45 (4H, m), 3.6-3.9 (10H, m), 5.0-5.15 (1H, m), 7.0-7.2 (4H, m)

Example 513-(β-D-Galactopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethyl-carbamoyl)-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using 2-aminoethanol instead of 1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.42 (6H, s), 1.8-1.9 (2H, m),2.19 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.28(2H, t, J=5.8 Hz), 3.45-3.65 (4H, m), 3.65-3.8 (5H, m), 3.86 (1H, d,J=2.7 Hz), 5.08 (1H, d, J=7.9 Hz), 7.0-7.15 (4H, m)

Example 523-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamino)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using N,N-dimethylethylenediamine instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.41 (6H, s), 1.8-1.9 (2H, m),2.19 (2H, t, J=7.7 Hz), 2.24 (6H, s), 2.42 (2H, t, J=6.8 Hz), 2.58 (2H,t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.28 (2H, t, J=6.8 Hz), 3.52 (1H, dd,J=9.7 Hz, 3.3 Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m), 3.8-3.9 (1H, m),5.08 (1H, d, J=7.4 Hz), 7.0-7.15 (4H, m)

Example 533-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamino)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand N,N-dimethylethylenediamine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.41 (6H, s), 1.8-1.9 (2H, m),2.18 (2H, t, J=7.5 Hz), 2.23 (6H, s), 2.41 (2H, t, J=6.8 Hz), 2.57 (2H,t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.2-3.45 (6H, m), 3.6-3.9 (4H, m),5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 543-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[3-(dimethylamino)propylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand N,N-dimethyl-1,3-propanediamine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.41 (6H, s), 1.6-1.7 (2H, m),1.8-1.9 (2H, m), 2.19 (2H, t, J=7.7 Hz), 2.22 (6H, s), 2.35 (2H, t,J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.18 (2H, t, J=6.6Hz), 3.3-3.45 (4H, m), 3.6-3.8 (3H, m), 3.8-3.9 (1H, m), 5.0-5.1 (1H,m), 7.0-7.15 (4H, m)

Example 553-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]propyl}-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-oxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}-phenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.16 (2H, t, J=7.5 Hz), 2.35-2.55 (6H, m), 2.58 (2H, t, J=7.3 Hz),2.85-3.0 (1H, m), 3.25-3.45 (4H, m), 3.55-3.9 (10H, m), 5.0-5.15 (1H,m), 7.0-7.15 (4H, m)

Example 564-[(4-{3-[1-(2-Aminoethylcarbamoyl)-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-3-(β-D-galactopyranosyl-oxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using ethylenediamine instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.41 (6H, s), 1.8-1.9 (2H, m),2.19 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.6 Hz), 2.7 (2H, t, J=5.9 Hz),2.85-2.95 (1H, m), 3.24 (2H, t, J=5.9 Hz), 3.51 (1H, dd, J=9.8 Hz, 3.2Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m), 3.86 (1H, d, J=3.2 Hz), 5.07(1H, d, J=7.9 Hz), 7.0-7.15 (4H, m)

Example 573-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using piperazine instead of 1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.1-2.2 (2H, m), 2.58 (2H, t, J=7.4 Hz), 2.65-2.8 (4H, m), 2.85-2.95(1H, m), 3.45-3.8 (11H, m), 3.8-3.9 (1H, m), 5.08 (1H, d, J=8.0 Hz),7.0-7.15 (4H, m)

Example 583-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.17 (2H, t, J=7.6 Hz), 2.5-2.85 (6H, m), 2.85-3.0 (1H, m), 3.25-3.45(4H, m), 3.5-3.9 (8H, m), 5.0-5.15 (1H, m), 7.0-7.15 (4H, m)

Example 593-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.8-1.9 (2H, m),2.1-2.2 (2H, m), 2.3 (3H, s), 2.35-2.6 (8H, m), 2.75-2.9 (1H, m),3.25-3.4 (4H, m), 3.45-3.75 (9H, m), 3.8 (1H, d, J=11.1 Hz), 4.95-5.05(1H, m), 6.8-7.0 (3H, m)

Example 603-(β-D-Galactopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using tris(hydroxymethyl)-aminomethane instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.52(1H, dd, J=9.7 Hz, 3.4 Hz), 3.55-3.9 (13H, m), 5.07 (1H, d, J=7.5 Hz),7.0-7.15 (4H, m)

Example 613-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using 1-methylpiperazine instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.42 (6H, s), 1.8-1.9 (2H, m),2.1-2.2 (2H, m), 2.25 (3H, s), 2.3-2.45 (4H, m), 2.58 (2H, t, J=7.4 Hz),2.85-2.95 (1H, m), 3.52 (1H, dd, J=9.6 Hz, 3.2 Hz), 3.55-3.8 (10H, m),3.8-3.9 (1H, m), 5.08 (1H, d, J=7.4 Hz), 7.0-7.15 (4H, m)

Example 623-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-isopropylpiperazin-1-yl)carbonyl]-1-(methyl)ethyl-carbamoyl}propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 48 using 1-isopropylpiperazine instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.03 (6H, d, J=6.6 Hz), 1.05-1.15 (6H, m), 1.42(6H, s), 1.8-1.95 (2H, m), 2.1-2.2 (2H, m), 2.35-2.7 (7H, m), 2.8-2.95(1H, m), 3.52 (1H, dd, J=9.8 Hz, 3.4 Hz), 3.55-3.8 (10H, m), 3.8-3.9(1H, m), 5.08 (1H, d, J=7.8 Hz), 7.0-7.15 (4H, m)

Example 633-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[(1E)-2-{1-[2-(dimethylamino)ethylcarbamoyl]-1-(methyl)ethylcarbamoyl}-vinyl]phenyl}methyl)-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole(1.2 g) in N,N-dimethylformamide (15 mL) and dichloromethane (10 mL) wasadded triethylamine (15 mL). To the mixture were added1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (0.56 g),1-hydroxy-benzotriazole (0.4 g), and a solution of2-amino-2-methyl-propionic acid (2.0 g) in water (15 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas neutralized by addition of 2 mol/L aqueous acetic acid solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and brine successively, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:ethyl acetate-dichloromethane/methanol=7/1-3/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{(1E)-2-[1-carboxy-1-(methyl)ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(0.44 g). This material was dissolved in N,N-dimethylformamide (0.3 mL).To the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.18 g), 1-hydroxybenzotriazole (0.13 g) andN,N-dimethyl-ethylenediamine (0.55 g), and the mixture was stirred atroom temperature overnight. To the reaction mixture was added 5 mol/Laqueous sodium hydroxide solution (1.5 mL), and the mixture was stirredat room temperature for 1 hour. To the reaction mixture was added aceticacid (1 mL), and the mixture was diluted with water (3 mL). Theinsoluble material was removed by filtration, and the filtrate waspurified by preparative reverse phase column chromatography (ShiseidoCAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minutelinear gradient, water/acetonitrile=90/10-10/60) to give the titlecompound (71 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.49 (6H, s), 2.27 (6H, s),2.46 (2H, t, J=6.7 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.9(4H, m), 5.05-5.15 (1H, m), 6.61 (1H, d, J=15.7 Hz), 7.2-7.3 (2H, m),7.35-7.5 (3H, m)

Example 643-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[(1E)-2-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}vinyl]-phenyl}methyl)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 63 using piperazine instead of N,N-dimethylethylenediamine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.51 (6H, s), 2.65-2.8 (4H, m),2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5-3.9 (8H, m), 5.05-5.15 (1H,m), 6.55 (1H, d, J=15.8 Hz), 7.2-7.3 (2H, m), 7.4-7.55 (3H, m)

Example 653-(β-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 63 using 1-(2-hydroxyethyl)piperazine instead ofN,N-dimethylethylenediamine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.51 (6H, s), 2.35-2.65 (6H, m),2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.55-3.9 (10H, m), 5.05-5.15 (1H,m), 6.55 (1H, d, J=15.8 Hz), 7.2-7.3 (2H, m), 7.4-7.5 (3H, m)

Example 663-(β-D-Glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using (S)-2-amino-1-propanol instead of glycinamidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (9H, m), 1.8-1.95 (2H, m), 2.17 (2H, t,J=7.7 Hz), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.25-3.5 (6H, m),3.6-3.8 (3H, m), 3.83 (1H, d, J=11.9 Hz), 3.85-4.0 (1H, m), 5.0-5.1 (1H,m), 7.0-7.15 (4H, m)

Example 673-(β-D-Galactopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand (S)-2-amino-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (9H, m), 1.8-1.95 (2H, m), 2.17 (2H, t,J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.35-3.55 (3H, m),3.55-3.65 (1H, m), 3.65-4.0 (7H, m), 5.0-5.15 (1H, m), 7.0-7.15 (4H, m)

Example 683-(β-D-Galactopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-di-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isoproypl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.25 (6H, s), 1.8-1.9 (2H, m),2.15 (2H, t, J=7.6 Hz), 2.56 (2H, t, J=7.5 Hz), 2.8-2.95 (1H, m),3.45-3.65 (4H, m), 3.65-3.8 (5H, m), 3.8-3.9 (1H, m), 5.0-5.1 (1H, m),7.0-7.15 (4H, m)

Example 694-[(4-{3-[(S)-5-Amino-5-(carbamoyl)pentylcarbamoyl]propyl}-phenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand (S)-2-benzyloxy-carbonylamino-6-aminohexanamide hydrochlorideinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.3-1.6 (5H, m), 1.6-1.75 (1H,m), 1.8-1.9 (2H, m), 2.15 (2H, t, J=7.7 Hz), 2.56 (2H, t, J=7.3 Hz),2.8-2.95 (1H, m), 3.15 (2H, t, J=7.0 Hz), 3.28 (1H, t, J=6.4 Hz), 3.52(1H, dd, J=9.8 Hz, 3.1 Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m), 3.8-3.9(1H, m), 5.08 (1H, d, J=7.9 Hz), 7.0-7.15 (4H, m)

Example 704-[(4-{3-[(S)-2-Amino-1-(methyl)ethylcarbamoyl]propyl}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole(1.6 g) in methanol (20 mL) was added 10% palladium-carbon powder, andthe mixture was stirred at room temperature under a hydrogen atmospherefor 3 hours. The insoluble material was removed by filtration, and thefiltrate was concentrated under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-carboxypropyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(1.5 g). This material was dissolved in N,N-dimethylformamide (15 mL).To the solution were added (S)-2-amino-1-propanol (0.89 g),1-hydroxybenzotriazole (0.48 g) and1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (0.68 g),and the mixture was stirred at room temperature overnight. The reactionmixture was poured into water, and the resulting mixture was extractedwith dichloromethane twice. The extracts were washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(1.64 g). The obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(0.19 g) was dissolved in dichloromethane (2 mL). To the solution wereadded triethyl-amine (0.058 mL) and methanesulfonyl chloride (0.032 mL)under ice-cooling, and the mixture was stirred at room temperature for 1hour. The reaction mixture was poured into water, and the resultingmixture was extracted with dichloromethane twice. The extracts werewashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure. The residue wasdissolved in N,N-dimethylformamide (1 mL). To the solution was addedsodium azide (0.18 g), and the mixture was stirred at 100° C. overnight.The reaction mixture was cooled to room temperature. Five mol/L aqueoussodium hydroxide solution (1.5 mL) was added to the mixture, and themixture was stirred for 1 hour. Acetic acid (1 mL) and water (2 mL) wereadded to the reaction mixture. The insoluble material was removed byfiltration, and the filtrate was purified by preparative reverse phasecolumn chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å,20×50 mm, flow rate 30 mL/minute linear gradient,water/acetonitrile=90/10-10/90) to give4-[(4-{3-[(1S)-2-azido-1-(methyl)ethylcarbamoyl]-propyl}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(18 mg). This material was dissolved in methanol (1 mL). To the solutionwas added 10% palladium-carbon powder (0.01 g), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 4 hours. Theinsoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give the title compound (12 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (9H, m), 1.8-1.95 (2H, m), 2.1-2.25 (2H,m), 2.5-2.65 (4H, m), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (5H,m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 714-[(4-{3-[2-Amino-1,1-di(methyl)ethylcarbamoyl]propyl}-phenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand 2-amino-1-benzyloxycarbonylamino-2-(methyl)propane instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.27 (6H, s), 1.8-1.9 (2H, m),2.16 (2H, t, J=7.7 Hz), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95 (3H, m), 3.51(1H, dd, J=9.8 Hz, 3.7 Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m), 3.8-3.9(1H, m), 5.08 (1H, d, J=7.7 Hz), 7.0-7.15 (4H, m)

Example 724-[(4-{3-[(R)-5-Amino-1-(hydroxymethyl)pentylcarbamoyl]-propyl}phenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazoleand (R)-2-amino-6-benzyloxycarbonylamino-1-hexanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazoleand glycinamide hydrochloride, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.2-1.7 (6H, m), 1.8-1.95 (2H,m), 2.2 (2H, t, J=7.5 Hz), 2.57 (2H, t, J=7.6 Hz), 2.65 (2H, t, J=7.3z),2.8-3.0 (1H, m), 3.4-3.65 (4H, m), 3.65-3.95 (7H, m), 5.0-5.15 (1H, m),7.0-7.15 (4H, m)

Example 733-(β-D-Glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using (S)-2-amino-1-propanol instead of ammonium chloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (9H, m), 2.8-2.95 (1H, m), 3.09 (2H, d,J=7.4 Hz), 3.25-3.55 (6H, m), 3.6-3.9 (4H, m), 3.9-4.0 (1H, m),5.05-5.15 (1H, m), 6.2-6.3 (1H, m), 6.47 (1H, d, J=15.9 Hz), 7.1-7.2(2H, m), 7.2-7.3 (2H, m)

Example 743-(β-D-Glucopyranosyloxy)-4-{[4-(3-{(S)-1-[2-hydroxy-1-(hydroxymethyl)ethylcarbamoyl]ethylcarbamoyl}propyl)-phenyl]methyl}-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole(7.13 g) in N,N-dimethyl-formamide (30 mL) were added1-hydroxybenzotriazole (2.31 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.25 g) andbenzyl(S)-2-aminopropionate (8.34 g), and the mixture was stirred atroom temperature overnight. The reaction mixture was poured into water,and the resulting mixture was extracted with ethyl acetate twice. Theextracts were washed with water and brine successively, and dried oversodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=1/2) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)-1-(benzyloxycarbonyl)ethylcarbamoyl]prop-1-enyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(3.25 g). This material was dissolved in methanol (40 mL). To thesolution was added 10% palladium-carbon powder (1.0 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere overnight.The insoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-1-(carboxy)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(2.25 g). To a solution of the obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-1-(carboxy)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(0.09 g) in N,N-dimethylformamide (0.5 mL) were added1-hydroxybenzotriazole (0.026 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.037 g)and 2-amino-1,3-propanediol (0.12 g), and the mixture was stirred atroom temperature for 1 hour. To the reaction mixture was added 5 mol/Laqueous sodium hydroxide solution (0.5 mL), and the mixture was stirredat room temperature for 1 hour. Acetic acid (0.3 mL) and water (1 mL)were added to the reaction mixture. The insoluble material was removedby filtration, and the filtrate was purified by preparative reversephase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120Å, 20×50 mm, flow rate 30 mL/minute linear gradient,water/acetonitrile=90/10-10/90) to give the title compound (0.017 g).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.32 (3H, d, J=6.8 Hz), 1.8-1.95(2H, m), 2.15-2.3 (2H, m), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m),3.25-3.45 (4H, m), 3.5-3.95 (9H, m), 4.25-4.35 (1H, m), 5.0-5.1 (1H, m),7.0-7.15 (4H, m)

Example 753-(β-D-Glucopyranosyloxy)-4-[(4-{3-[(S)-1-(2-hydroxyethyl-carbamoyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 74 using 2-aminoethanol instead of 2-amino-1,3-propanediol.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.31 (3H, d, J=7.0 Hz), 1.8-1.95(2H, m), 2.15-2.25 (2H, m), 2.58 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m),3.25-3.45 (6H, m), 3.58 (2H, t, J=5.7 Hz), 3.6-3.8 (3H, m), 3.83 (1H, d,J=11.9 Hz), 4.25-4.35 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Example 763-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{(S)-1-[(4-methylpiperazin-1-yl)carbonyl]ethylcarbamoyl}propyl)-phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 74 using 1-methylpiperazine instead of 2-amino-1,3-propanediol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.26 (3H, d, J=7.0 Hz), 1.8-1.95(2H, m), 2.2 (2H, t, J=7.4 Hz), 2.25-2.55 (7H, m), 2.57 (2H, t, J=7.6Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.45-3.75 (6H, m), 3.77 (1H,d, J=16.0 Hz), 3.83 (1H, d, J=11.7 Hz), 4.75-4.9 (1H, m), 5.0-5.1 (1H,m), 7.0-7.15 (4H, m)

Example 773-(β-D-Glucopyranosyloxy)-4-[(4-{3-[(S)-1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}ethylcarbamoyl]propyl}-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 74 using 1-(2-hydroxyethyl)piperazine instead of2-amino-1,3-propanediol.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.26 (3H, d, J=6.9 Hz), 1.8-1.95(2H, m), 2.2 (2H, t, J=7.4 Hz), 2.4-2.65 (8H, m), 2.85-2.95 (1H, m),3.2-3.45 (4H, m), 3.45-3.75 (8H, m), 3.77 (1H, d, J=16.4 Hz), 3.83 (1H,d, J=11.9 Hz), 4.75-4.9 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)

Reference Example 22 (4-Benzyloxy-2-methylphenyl)methanol

To a solution of 4-bromo-3-methylphenol (10 g) in N,N-dimethylformamide(50 mL) were added potassium carbonate (8.87 g) and benzyl bromide (6.36mL), and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with diethyl ether. The organic layer was washed with waterand dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6g). This material was dissolved in tetrahydrofuran (200 mL). To thesolution was added n-butyl lithium (2.66 mol/L n-hexane solution, 21.7mL) at −78° C. under an argon atmosphere, and the mixture was stirredfor 10 minutes. To the reaction mixture was added N,N-dimethylformamide(10.1 mL), and the mixture was allowed to warm to 0° C. and stirred for30 minutes. The reaction mixture was poured into water, and theresulting mixture was extracted with diethyl ether. The organic layerwas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure to give4-benzyloxy-2-methylbenzaldehyde. This material was dissolved in ethanol(100 mL). To the solution was added sodium borohydride (1.99 g), and themixture was stirred at room temperature overnight. To the reactionmixture was added methanol, and the resulting mixture was concentratedunder reduced pressure. To the residue was added a saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withdiethylether. The organic layer was washed with a saturated aqueoussodium hydrogen carbonate solution, water and brine successively, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethylacetate=6/1-3/1-1/1) to give thetitle compound (10.5 g).

¹H-NMR (CDCl₃) δ ppm: 1.37 (1H, t, J=5.8 Hz), 2.36 (3H, s), 4.64 (2H, d,J=5.8 Hz), 5.06 (2H, s), 6.79 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.84 (1H, d,J=2.4 Hz), 7.23 (1H, d, J=8.4 Hz), 7.25-7.45 (5H, m)

Reference Example 234-[(4-Benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of (4-benzyloxy-2-methylphenyl)methanol (10.5 g) intetrahydrofuran (80 mL) were added triethylamine (7.36 mL) andmethanesulfonyl chloride (3.91 mL) under ice-cooling. After the mixturewas stirred for 1 hour, the insoluble material was removed byfiltration. The obtained solution of (4-benzyloxy-2-methylphenyl)methylmesylate in tetrahydrofuran was added to a suspension of sodium hydride(60%, 2.11 g) and ethyl 4-methyl-3-oxopentanoate (7.99 g) intetrahydrofuran (160 mL), and the mixture was refluxed for 15 hours. Tothe reaction mixture was added 1 mol/L hydrochloric acid, and theresulting mixture was extracted with diethyl ether. The organic layerwas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure. The residue was dissolved intoluene (30 mL). Hydrazine monohydrate (6.68 mL) was added to thesolution, and the mixture was stirred at 100° C. overnight. The reactionmixture was poured into water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was treated with n-hexane. The precipitatedcrystals were collected by filtration, and dried under reduced pressureto give the title compound (12.3 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (6H, d, J=6.8 Hz), 2.24 (3H, s), 2.65-2.8(1H, m), 3.44 (2H, s), 5.02 (2H, s), 6.69 (1H, dd, J=8.7 Hz, 2.4 Hz),6.75-6.85 (2H, m), 7.25-7.45 (5H, m)

Reference Example 244-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (Kunz, H.;Harreus, A. Liebigs Ann. Chem. 1982, 41-48 Velarde, S.; Urbina, J.;Pena, M. R. J. Org. Chem. 1996, 61, 9541-9545) instead of4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.04 (9H, s), 1.05-1.2 (33H, m), 2.27 (3H, s),2.7-2.85 (1H, m), 3.45-3.6 (2H, m), 3.8-3.9 (1H, m), 4.11 (1H, dd,J=12.6 Hz, 4.8 Hz), 4.17 (1H, dd, J=12.6 Hz, 1.8 Hz), 5.0 (2H, s),5.15-5.3 (2H, m), 5.37 (1H, t, J=9.5 Hz), 5.65 (1H, d, J=7.8 Hz), 6.64(1H, dd, J=8.4 Hz, 2.8 Hz), 6.77 (1H, d, J=2.8 Hz), 6.83 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Reference Example 254-[(4-Hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(5 g) was dissolved in tetrahydrofuran (18 mL). To the solution wasadded 10% palladium-carbon powder (500 mg), and the mixture was stirredat room temperature under a hydrogen atmosphere for 3 hours. Theinsoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(4.45 g).

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 2.24 (3H, s), 2.7-2.85 (1H, m),3.52 (2H, s), 3.8-3.9 (1H, m), 4.09 (1H, dd, J=12.4 Hz, 4.7 Hz), 4.15(1H, dd, J=12.4 Hz, 1.9 Hz), 4.6 (1H, s), 5.15-5.25 (2H, m), 5.36 (1H,t, J=9.2 Hz), 5.65 (1H, d, J=8.0 Hz), 6.5 (1H, dd, J=8.3 Hz, 2.9 Hz),6.61 (1H, d, J=2.9 Hz), 6.78 (1H, d, J=8.3 Hz)

Reference Example 26 Benzyl 4-bromobutyrate

To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) andtriphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was addeddiethyl azodicarboxylate (40% toluene solution, 2.88 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was poured into water, and the resulting mixture was extractedwith diethylether. The extract was washed with water and brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the titlecompound (0.69 g).

¹H-NMR (CDCl₃) δ ppm: 2.15-2.25 (2H, m), 2.56 (2H, t, J=7.1 Hz), 3.46(2H, t, J=6.5 Hz), 5.13 (2H, s), 7.25-7.4 (5H, m)

Reference Example 274-({4-[3-(Benzyloxycarbonyl)propoxy]-2-methylphenyl}-methyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(0.2 g) in N,N-dimethylformamide (3 mL) were added benzyl4-bromobutyrate (0.1 g), cesium carbonate (0.18 g) and a catalyticamount of sodium iodide, and the mixture was stirred at room temperatureovernight. The reaction mixture was poured into water, and the resultingmixture was extracted with ethylacetate. The extract was washed withwater and brine, and dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethylacetate=3/1-2/1) to give the title compound (0.16 g).

¹H-NMR (CDCl₃) δ ppm: 1.04 (9H, s), 1.05-1.2 (33H, m), 2.05-2.15 (2H,m), 2.25 (3H, s), 2.56 (2H, t, J=7.3 Hz), 2.7-2.85 (1H, m), 3.53 (2H,s), 3.8-3.9 (1H, m), 3.94 (2H, t, J=6.2 Hz), 4.1 (1H, dd, J=12.5 Hz, 4.1Hz), 4.16 (1H, dd, J=12.5 Hz, 2.0 Hz), 5.13 (2H, s), 5.15-5.25 (2H, m),5.36 (1H, t, J=9.6 Hz), 5.65 (1H, d, J=8.1 Hz), 6.54 (1H, dd, J=8.5 Hz,2.7 Hz), 6.64 (1H, d, J=2.7 Hz), 6.81 (1H, d, J=8.5 Hz), 7.25-7.4 (5H,m)

Reference Example 281,2-Dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 23 using 4-iodobenzyl alcohol instead of(4-benzyloxy-2-methylphenyl)methanol.

¹H-NMR (CD₃OD) δ ppm: 1.12 (6H, d, J=7.3 Hz), 2.8-2.95 (1H, m), 3.63(2H, s), 6.9-7.0 (2H, m), 7.5-7.6 (2H, m)

Reference Example 293-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-iodophenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one andacetobromo-α-D-galactose instead of4-{[4-(2-benzyloxy-carbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.15-1.2 (6H, m), 1.88 (3H, s), 1.99 (3H, s), 2.03(3H, s), 2.18 (3H, s), 2.8-2.95 (1H, m), 3.58 (1H, d, J=16.0 Hz), 3.65(1H, d, J=16.0 Hz), 4.0-4.1 (1H, m), 4.15-4.25 (2H, m), 5.09 (1H, dd,J=10.7 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.56 (1H, d, J=8.3 Hz), 6.85-6.95(2H, m), 7.5-7.6 (2H, m)

Reference Example 30 {4-[2-(Benzyloxycarbonyl)ethoxy]phenyl}methanol

To a mixture of 3-[4-(hydroxymethyl)phenoxy]propionic acid (0.98 g) andpotassium carbonate (0.9 g) in N,N-dimethyl-formamide (5 mL) was addedbenzyl bromide (0.65 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andthe resulting mixture was extracted with diethyl ether. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=2/1-1/1) to give the title compound (1.1 g).

¹H-NMR (CDCl₃) δ ppm: 1.5-1.55 (1H, m), 2.85 (2H, t, J=6.4 Hz), 4.28(2H, t, J=6.4 Hz), 4.62 (2H, d, J=5.9 Hz), 5.18 (2H, s), 6.85-6.9 (2H,m), 7.25-7.4 (7H, m)

Reference Example 31 4-Hydroxy-2-methylbenzaldehyde

To a solution of 4-bromo-3-methylphenol (14 g) and N,N-diisopropylamine(39.1 mL) in dichloromethane (150 mL) was added chloromethyl methylether (11.4 mL) under ice-cooling, and the mixture was stirred at roomtemperature for 5 days. The reaction mixture was poured into a saturatedaqueous citric acid solution, and the resulting mixture was extractedwith diethyl ether. The extract was washed with water, 1 mol/L aqueoussodium hydroxide solution, water and brine successively, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 4-bromo-3-methyl-1-(methoxymethoxy)benzene (16.7 g). Thismaterial was dissolved in tetrahydrofuran (250 mL). To the solution wasadded n-butyl lithium (2.64 mol/L n-hexane solution, 32.7 mL) at −78° C.under an argon atmosphere, and the mixture was stirred at the sametemperature for 15 minutes. To the reaction mixture was addedN,N-dimethylformamide (16.6 mL), and the mixture was stirred underice-cooling for 1 hour. The reaction mixture was poured into a saturatedaqueous ammonium chloride solution, and the resulting mixture wasextracted with diethyl ether. The extract was washed with a saturatedaqueous sodium hydrogen carbonate solution and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 2-methyl-4-(methoxymethoxy)benzaldehyde (12.9 g). This materialwas dissolved in tetrahydrofuran (70 mL)-methanol (10 mL). To thesolution was added concentrated hydrochloric acid (6 mL), and themixture was stirred at 50° C. for 1.5 hours. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure. The residue was dissolved in ethylacetate (30 mL) with heating at 60° C. n-Hexane (100 mL) was added tothe solution gently, and the mixture was stirred at the same temperaturefor 10 minutes. The mixture was cooled to room temperature. n-Hexane(170 mL) was added to the mixture, and the resulting mixture was stirredovernight. The precipitated crystals were collected by filtration, andwashed with n-hexane and dried under reduced pressure to give the titlecompound (5.6 g).

¹H-NMR (CDCl₃) δ ppm: 2.63 (3H, s), 5.47 (1H, s), 6.7 (1H, d, J=2.3 Hz),6.79 (1H, dd, J=8.4 Hz, 2.3 Hz), 7.73 (1H, d, J=8.4 Hz), 10.11 (1H, s)

Reference Example 32 4-(2-Carboxyethoxy)-2-methylbenzaldehyde

To a mixture of 4-hydroxy-2-methylbenzaldehyde (5 g) and potassiumtert-butoxide (4.12 g) in tetrahydrofuran (60 mL) was addedβ-propiolactone (4.6 mL), and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was poured into 1 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure. The residue was suspended in ethyl acetate (20 mL)-n-hexane(100 mL). The insoluble material was collected by filtration, and washedwith n-hexane and dried under reduced pressure to give the titlecompound (7.2 g).

¹H-NMR (CDCl₃) δ ppm: 2.65 (3H, s), 2.89 (2H, t, J=6.4 Hz), 4.32 (2H, t,J=6.4 Hz), 6.76 (1H, d, J=2.5 Hz), 6.85 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.76(1H, d, J=8.7 Hz), 10.12 (1H, s)

Reference Example 334-[2-(Benzyloxycarbonyl)ethoxy]-2-methylbenzaldehyde

To a suspension of 4-(2-carboxyethoxy)-2-methyl-benzaldehyde (7.2 g) andpotassium carbonate (14.3 g) in N,N-dimethylformamide (70 mL) was addedbenzyl bromide (8.2 mL) at room temperature, and the mixture was stirredovernight. The reaction mixture was poured into water, and the resultingmixture was extracted with diethyl ether. The extract was washed withwater and brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethylacetate=4/1-3/1) to give the title compound (6.47 g).

¹H-NMR (CDCl₃) δ ppm: 2.64 (3H, s), 2.88 (2H, t, J=6.3 Hz), 4.34 (2H, t,J=6.3 Hz), 5.19 (2H, s), 6.73 (1H, d, J=2.4 Hz), 6.83 (1H, dd, J=8.5 Hz,2.4 Hz), 7.3-7.4 (5H, m), 7.75 (1H, d, J=8.5 Hz), 10.12 (1H, s)

Reference Example 34{4-[2-(Benzyloxycarbonyl)ethoxy]-2-methylphenyl}methanol

The title compound was prepared in a similar manner to that described inReference Example 10 using4-[2-(benzyloxy-carbonyl)ethoxy]-2-methylbenzaldehyde instead of4-(2-benzyl-oxycarbonyl-2-methylpropoxy)benzaldehyde.

¹H-NMR (CDCl₃) δ ppm: 1.38 (1H, t, J=5.7 Hz), 2.35 (3H, s), 2.84 (2H, t,J=6.4 Hz), 4.26 (2H, t, J=6.4 Hz), 4.63 (2H, d, J=5.7 Hz), 5.18 (2H, s),6.7-6.75 (2H, m), 7.22 (1H, d, J=8.2 Hz), 7.3-7.4 (5H, m)

Reference Example 354-({4-[2-(Benzyloxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using{4-[2-(benzyloxy-carbonyl)ethoxy]phenyl}methanol instead of[4-(2-benzyloxy-carbonyl-2-methylpropoxy)phenyl]methanol.

¹H-NMR (DMSO-d₆) δ ppm: 1.05-1.1 (6H, m), 2.75-2.85 (3H, m), 3.5 (2H,s), 4.16 (2H, t, J=5.9 Hz), 5.14 (2H, s), 6.75-6.8 (2H, m), 7.0-7.05(2H, m), 7.3-7.4 (5H, m)

Reference Example 364-({4-[2-(Benzyloxycarbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using{4-[2-(benzyloxy-carbonyl)ethoxy]-2-methylphenyl}methanol instead of[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methanol.

¹H-NMR (CDCl₃) δ ppm: 1.12 (6H, d, J=6.8 Hz), 2.3 (3H, s), 2.75-2.9 (3H,m), 3.6 (2H, s), 4.23 (2H, t, J=6.2 Hz), 5.17 (2H, s), 6.62 (1H, dd,J=8.5 Hz, 2.7 Hz), 6.7 (1H, d, J=2.7 Hz), 6.94 (1H, d, J=8.5 Hz),7.25-7.4 (5H, m)

Reference Example 373-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-({4-[2-(benzyl-oxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.87 (3H, s), 2.01 (3H, s), 2.03(3H, s), 2.06 (3H, s), 2.82 (2H, t, J=6.4 Hz), 2.85-2.95 (1H, m), 3.57(1H, d, J=15.9 Hz), 3.63 (1H, d, J=15.9 Hz), 3.8-3.9 (1H, m), 4.1-4.15(1H, m), 4.22 (2H, t, J=6.4 Hz), 4.31 (1H, dd, J=12.4 Hz, 4.0 Hz), 5.16(2H, s), 5.2-5.3 (3H, m), 5.58 (1H, d, J=7.6 Hz), 6.7-6.8 (2H, m),7.0-7.05 (2H, m), 7.3-7.4 (5H, m)

Reference Example 383-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[2-(benzyloxycarbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-({4-[2-(benzyl-oxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-galactose instead of4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.88 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.17 (3H, s), 2.8-2.9 (3H, m), 3.58 (1H, d, J=16.1 Hz), 3.65(1H, d, J=16.1 Hz), 4.0-4.25 (5H, m), 5.09 (1H, dd, J=10.4 Hz, 3.5 Hz),5.17 (2H, s), 5.4-5.45 (2H, m), 5.55 (1H, d, J=8.2 Hz), 6.7-6.8 (2H, m),7.0-7.05 (2H, m), 7.25-7.35 (5H, m)

Reference Example 393-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-({4-[2-(benzyl-oxycarbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(2-benzyloxycarbonyl-2-methyl-propoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.8 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.25 (3H, s), 2.7-2.85 (3H, m), 3.49 (1H, d,J=16.2 Hz), 3.59 (1H, d, J=16.2 Hz), 3.8-3.9 (1H, m), 4.12 (1H, dd,J=12.4 Hz, 2.3 Hz), 4.21 (2H, t, J=6.6 Hz), 4.3 (1H, dd, J=12.4 Hz, 4.0Hz), 5.15-5.3 (5H, m), 5.56 (1H, d, J=8.0 Hz), 6.57 (1H, dd, J=8.5 Hz,2.4 Hz), 6.67 (1H, d, J=2.4 Hz), 6.8 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)

Reference Example 403-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 13 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxy-carbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.89 (3H, s), 1.97 (3H, s), 2.0(3H, s), 2.02 (3H, s), 2.71 (2H, t, J=6.2 Hz), 2.85-2.95 (1H, m), 3.6(2H, s), 3.9-3.95 (1H, m), 4.1-4.15 (1H, m), 4.18 (2H, t, J=6.2 Hz), 4.3(1H, dd, J=12.4 Hz, 4.0 Hz), 5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48(1H, d, J=8.0 Hz), 6.75-6.8 (2H, m), 7.0-7.05 (2H, m)

Reference Example 413-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 13 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[2-(benzyloxy-carbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.9 (3H, s), 1.95 (3H, s), 1.99(3H, s), 2.16 (3H, s), 2.71 (2H, t, J=6.1 Hz), 2.85-2.95 (1H, m), 3.61(2H, s), 4.05-4.2 (5H, m), 5.19 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.25-5.35(1H, m), 5.4-5.45 (1H, m), 5.46 (1H, d, J=8.1 Hz), 6.75-6.8 (2H, m),7.0-7.05 (2H, m)

Reference Example 423-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 13 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxy-carbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.82 (3H, s), 1.96 (3H, s), 2.0(3H, s), 2.02 (3H, s), 2.26 (3H, s), 2.7 (2H, t, J=6.2 Hz), 2.75-2.9(1H, m), 3.53 (1H, d, J=16.4 Hz), 3.58 (1H, d, J=16.4 Hz), 3.85-3.95(1H, m), 4.08 (1H, dd, J=12.4 Hz, 2.4 Hz), 4.17 (2H, t, J=6.2 Hz), 4.28(1H, dd, J=12.4 Hz, 4.1 Hz), 5.0-5.15 (2H, m), 5.27 (1H, t, J=9.6 Hz),5.43 (1H, d, J=7.9 Hz), 6.61 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.71 (1H, d,J=2.5 Hz), 6.77 (1H, d, J=8.5 Hz)

Reference Example 434-{[4-(3-Carboxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 25 using4-({4-[3-(benzyl-oxycarbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.04 (9H, s), 1.05-1.2 (33H, m), 2.05-2.15 (2H,m), 2.25 (3H, s), 2.5-2.6 (2H, m), 2.7-2.8 (1H, m), 3.52 (2H, s),3.8-3.9 (1H, m), 3.95-4.0 (2H, m), 4.05-4.15 (1H, m), 4.17 (1H, dd,J=12.4 Hz, 1.9 Hz), 5.15-5.3 (2H, m), 5.36 (1H, t, J=9.4 Hz), 5.53 (1H,d, J=8.3 Hz), 6.57 (1H, dd, J=8.4 Hz, 2.7 Hz), 6.67 (1H, d, J=2.7 Hz),6.81 (1H, d, J=8.4 Hz)

Reference Example 44 Benzyl 2-amino-2-methylpropinate hydrochloride

To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propionic acid(4.06 g) in N,N-dimethylformamide (40 mL) were added potassium carbonate(4.15 g) and benzyl bromide (2.85 mL), and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was poured intowater, and the resulting mixture was extracted with ethylacetate. Theextract was washed with water and brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure. The residue(solid) was treated with n-hexane and collected by filtration. Thecrystals were dried under reduced pressure to give benzyl2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g). Hydrochloricacid (4 mol/L 1,4-dioxane solution, 15 mL) was added to the obtainedbenzyl 2-(tert-butoxycarbonylamino)-2-methyl-propionate (4.44 g), andthe mixture was stirred at room temperature overnight. The reactionmixture was diluted with diethyl ether, and the resulting mixture wasstirred for 1 hour. The insoluble material was collected by filtration,and washed with diethyl ether and dried under reduced pressure to givethe title compound (3.4 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.49 (6H, s), 5.25 (2H, s), 7.3-7.45 (5H, m),8.54 (3H, brs)

Reference Example 453-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.14 g) in N,N-dimethyl-formamide (3 mL) were added benzyl2-amino-2-methylpropionate hydrochloride (57 mg), 1-hydroxybenzotriazole(31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60mg) and triethylamine (0.087 mL), and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=40/1-20/1) to give the title compound (0.15 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.15 (6H, m), 1.56 (6H, s), 1.81 (3H, s), 1.99(3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.25 (3H, s), 2.6 (2H, t, J=6.1Hz), 2.75-2.85 (1H, m), 3.5 (1H, d, J=16.7 Hz), 3.59 (1H, d, J=16.7 Hz),3.8-3.9 (1H, m), 4.05-4.2 (3H, m), 4.29 (1H, dd, J=12.5 Hz, 4.0 Hz),5.1-5.3 (5H, m), 5.56 (1H, d, J=8.1 Hz), 6.53 (1H, brs), 6.57 (1H, dd,J=8.5 Hz, 2.5 Hz), 6.67 (1H, d, J=2.5 Hz), 6.8 (1H, d, J=8.5 Hz),7.25-7.4 (5H, m)

Reference Example 463-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(benzyloxycarbonyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 45 using benzyl(S)-2-amino-propionatep-toluenesulfonic acid salt instead of benzyl 2-amino-2-methylpropionatehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.38 (3H, d, J=7.3 Hz), 1.82(3H, s), 1.95 (3H, s), 2.0 (3H, s), 2.01 (3H, s), 2.25 (3H, s), 2.6-2.7(2H, m), 2.75-2.9 (1H, m), 3.52 (1H, d, J=16.5 Hz), 3.58 (1H, d, J=16.5Hz), 3.85-3.95 (1H, m), 4.07 (1H, dd, J=12.2 Hz, 2.5 Hz), 4.1-4.2 (2H,m), 4.27 (1H, dd, J=12.2 Hz, 4.2 Hz), 4.4-4.5 (1H, m), 5.0-5.2 (4H, m),5.28 (1H, t, J=9.5 Hz), 5.43 (1H, d, J=7.9 Hz), 6.58 (1H, dd, J=8.5 Hz,2.2 Hz), 6.69 (1H, d, J=2.2 Hz), 6.76 (1H, d, J=8.5 Hz), 7.25-7.4 (5H,m)

Reference Example 474-[(4-{3-[1-Benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]-propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 45 using4-{[4-(3-carboxy-propoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.52 (6H, s), 1.95-2.1 (2H, m),2.25 (3H, s), 2.34 (2H, t, J=7.3 Hz), 2.7-2.85 (1H, m), 3.52 (2H, s),3.8-3.95 (3H, m), 4.05-4.2 (2H, m), 5.1-5.25 (4H, m), 5.36 (1H, t, J=9.1Hz), 5.65 (1H, d, J=8.3 Hz), 6.05 (1H, brs), 6.53 (1H, dd, J=8.2 Hz, 2.5Hz), 6.65 (1H, d, J=2.5 Hz), 6.81 (1H, d, J=8.2 Hz), 7.25-7.4 (5H, m)

Reference Example 483-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]-ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(0.15 g) was dissolved in methanol (5 mL). To the solution was added 10%palladium-carbon powder (50 mg), and the mixture was stirred at roomtemperature under a hydrogen atmosphere overnight. The insolublematerial was removed by filtration, and the solvent of the filtrate wasremoved under reduced pressure to give the title compound (0.13 g).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.47 (6H, s), 1.82 (3H, s),1.96 (3H, s), 2.0 (3H, s), 2.02 (3H, s), 2.26 (3H, s), 2.6 (2H, t, J=6.3Hz), 2.75-2.9 (1H, m), 3.52 (1H, d, J=16.4 Hz), 3.58 (1H, d, J=16.4 Hz),3.85-3.95 (1H, m), 4.07 (1H, dd, J=12.4 Hz, 2.2 Hz), 4.16 (2H, t, J=6.3Hz), 4.27 (1H, dd, J=12.4 Hz, 4.0 Hz), 5.0-5.15 (2H, m), 5.28 (1H, t,J=9.5 Hz), 5.43 (1H, d, J=8.2 Hz), 6.61 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.71(1H, d, J=2.6 Hz), 6.77 (1H, d, J=8.5 Hz)

Reference Example 493-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(carboxy)ethylcarbamoyl]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(benzyloxy-carbonyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.39 (3H, d, J=7.3 Hz), 1.82(3H, s), 1.96 (3H, s), 2.0 (3H, s), 2.02 (3H, s), 2.26 (3H, s), 2.6-2.7(2H, m), 2.75-2.9 (1H, m), 3.52 (1H, d, J=16.6 Hz), 3.58 (1H, d, J=16.6Hz), 3.85-3.95 (1H, m), 4.07 (1H, dd, J=12.4 Hz, 2.5 Hz), 4.1-4.25 (2H,m), 4.27 (1H, dd, J=12.4 Hz, 4.0 Hz), 4.4 (1H, q, J=7.3 Hz), 5.0-5.15(2H, m), 5.28 (1H, t, J=9.4 Hz), 5.43 (1H, d, J=8.0 Hz), 6.62 (1H, dd,J=8.3 Hz, 2.7 Hz), 6.72 (1H, d, J=2.7 Hz), 6.77 (1H, d, J=8.3 Hz)

Reference Example 504-[(4-{3-[1-Carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 48 using4-[(4-{3-[1-benzyl-oxycarbonyl-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-benzyloxy-carbonyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (42H, m), 1.44 (6H, s), 1.95-2.05 (2H,m), 2.26 (3H, s), 2.35 (2H, t, J=7.4 Hz), 2.75-2.85 (1H, m), 3.5-3.6(2H, m), 3.9-4.0 (3H, m), 4.09 (1H, dd, J=12.4 Hz, 1.8 Hz), 4.17 (1H,dd, J=12.4 Hz, 4.2 Hz), 5.05-5.2 (2H, m), 5.39 (1H, t, J=9.5 Hz), 5.58(1H, d, J=7.9 Hz), 6.58 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6Hz), 6.8 (1H, d, J=8.4 Hz)

Reference Example 513-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)ethylcarbamoyl]butyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole

A mixture of3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-4-[(4-iodophenyl)methyl]-5-isopropyl-1H-pyrazole(0.43 g), 4-pentynoic acid (94 mg),tetrakis-(triphenylphosphine)palladium(0) (37 mg), copper(I) iodide (12mg) and tiethylamine (0.45 mL) in tetrahydrofuran (5 mL) was stirred atroom temperature under an argon atmosphere overnight. The reactionmixture was poured into 0.5 mol/L hydrochloric acid, and the resultingmixture was extracted with ethyl acetate. The extract was washed withwater and brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethylacetate=1/2-ethyl acetate) to give3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(4-carboxybut-1-ynyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.37 g). This material was dissolved in N,N-dimethyl-formamide (6 mL).To the solution were added benzyl 2-amino-2-methylpropionatehydrochloride (0.15 g), 1-hydroxybenzo-triazole (86 mg),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (0.22 g) andtriethylamine (0.32 mL), and the mixture was stirred at room temperatureovernight. The reaction mixture was poured into 0.5 mol/L hydrochloricacid, and the resulting mixture was extracted with ethyl acetate. Theextract was washed with water, a saturated aqueous sodium hydrogencarbonate solution and brine successively, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=20/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-4-[(4-{4-[1-benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]but-1-ynyl}phenyl)methyl]-5-isopropyl-1H-pyrazole(0.36 g). This material was dissolved in methanol (5 mL). To thesolution was added 10% palladium-carbon powder (50 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 2 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(0.31 g).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.44 (6H, s), 1.55-1.65 (4H, m),1.88 (3H, s), 1.95 (3H, s), 1.99 (3H, s), 2.1-2.2 (5H, m), 2.5-2.6 (2H,m), 2.85-3.0 (1H, m), 3.55-3.7 (2H, m), 4.05-4.2 (3H, m), 5.19 (1H, dd,J=10.4 Hz, 3.5 Hz), 5.25-5.35 (1H, m), 5.4-5.45 (1H, m), 5.46 (1H, d,J=8.1 Hz), 7.0-7.1 (4H, m)

Example 784-[(4-{2-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.2 g) in N,N-dimethyl-formamide (3 mL) were added2-amino-2-methylpropionamide (47 mg), 1-hydroxybenzotriazole (50 mg),1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (118 mg)and triethylamine (0.13 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over an hydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=20/1-10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(0.12 g). This material was dissolved in methanol (3 mL). To thesolution was added sodium methoxide (28% methanol solution, 0.06 mL),and the mixture was stirred at room temperature for 1 hour. To thereaction mixture was added acetic acid (0.1 mL), and the resultingmixture was concentrated under reduced pressure. The residue waspurified by solid phase extraction on ODS (washing solvent: distilledwater, eluent: methanol) to give the title compound (80 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.47 (6H, s), 2.29 (3H, s),2.62 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.6-3.75(3H, m), 3.81 (1H, d, J=11.9 Hz), 4.18 (2H, t, J=6.1 Hz), 4.95-5.05 (1H,m), 6.63 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.72 (1H, d, J=2.4 Hz), 6.86 (1H,d, J=8.4 Hz)

Example 794-[(4-{2-[1-Carbamoyl-1-(methyl)ethylcarbamoyl]ethoxy}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.5-1.15 (6H, m), 1.47 (6H, s), 2.63 (2H, t, J=6.2Hz), 2.85-2.95 (1H, m), 3.3-3.4 (4H, m), 3.6-3.75 (3H, m), 3.8-3.85 (1H,m), 4.19 (2H, t, J=6.2 Hz), 5.05-5.1 (1H, m), 6.8-6.85 (2H, m), 7.1-7.15(2H, m)

Example 803-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)ethylcarbamoyl]ethoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-propionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.27 (6H, s), 2.59 (2H, t, J=6.2Hz), 2.85-2.95 (1H, m), 3.3-3.4 (4H, m), 3.57 (2H, s), 3.6-3.85 (4H, m),4.16 (2H, t, J=6.2 Hz), 5.05-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15(2H, m)

Reference Example 52 1-(2-Amino-2-methylpropionyl)-4-methylpiperazine

To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (2.37g) in tetrahydrofuran (20 mL) was added 1,1′-carbonylbis-1H-imidazole(1.78 g), and the mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was added 1-methylpiperazine (2.0 mL), and themixture was stirred at 40° C. for 3.5 days. To the reaction mixture wasadded methanol, and the resulting mixture was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: dichloromethane/methanol=20/1) to give1-(2-benzyloxycarbonylamino-2-methyl-propionyl)-4-methylpiperazine (1.99g). This material was dissolved in methanol (10 mL). To the solution wasadded 10% palladium-carbon powder (0.4 g), and the mixture was stirredat room temperature under a hydrogen atmosphere for 3 hours. Theinsoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(1.14 g).

¹H-NMR (CD₃OD) δ ppm: 1.39 (6H, s), 2.3 (3H, s), 2.44 (4H, t, J=5.1 Hz),3.77 (4H, brs)

Reference Example 53 2-(2-Amino-2-methylpropionylamino)ethanol

The title compound was prepared in a similar manner to that described inReference Example 52 using 2-aminoethanol instead of 1-methylpiperazine.

¹H-NMR (CD₃OD) δ ppm: 1.31 (6H, s), 3.25-3.35 (2H, m), 3.6 (2H, t, J=5.8Hz)

Example 813-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazoleand 1-(2-amino-2-methylpropionyl)-4-methylpiperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxy-ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.45 (6H, s), 2.2 (3H, s),2.3-2.5 (4H, m), 2.6 (2H, t, J=5.7 Hz), 2.85-2.95 (1H, m), 3.3-3.4 (4H,m), 3.6-3.9 (8H, m), 4.18 (2H, t, J=5.7 Hz), 5.05-5.1 (1H, m), 6.75-6.85(2H, m), 7.1-7.15 (2H, m)

Example 823-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand 1-(2-amino-2-methyl-propionyl)-4-methylpiperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.45 (6H, s), 2.17 (3H, s), 2.35(4H, brs), 2.6 (2H, t, J=5.6 Hz), 2.85-2.95 (1H, m), 3.52 (1H, dd, J=9.7Hz, 3.2 Hz), 3.55-3.9 (11H, m), 4.18 (2H, t, J=5.6 Hz), 5.08 (1H, d,J=7.6 Hz), 6.75-6.85 (2H, m), 7.05-7.2 (2H, m)

Example 833-(β-D-Glucopyranosyloxy)-4-[(4-{2-[1-(2-hydroxyethyl-carbamoyl)-1-(methyl)ethylcarbamoyl]ethoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-(2-amino-2-methylpropionyl-amino)ethanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-propionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.45 (6H, s), 2.63 (2H, t, J=6.2Hz), 2.85-2.95 (1H, m), 3.24 (2H, t, J=5.9 Hz), 3.3-3.4 (4H, m), 3.51(2H, t, J=5.9 Hz), 3.6-3.85 (4H, m), 4.19 (2H, t, J=6.2 Hz), 5.05-5.1(1H, m), 6.8-6.85 (2H, m), 7.1-7.15 (2H, m)

Example 843-(β-D-Glucopyranosyloxy)-4-[(4-{2-[(S)-2-hydroxy-1-(methyl)ethylcarbamoyl]ethoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand (S)-2-amino-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-oxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (9H, m), 2.55-2.65 (2H, m), 2.85-2.95(1H, m), 3.3-3.4 (4H, m), 3.44 (1H, dd, J=10.9 Hz, 5.7 Hz), 3.49 (1H,dd, J=10.9 Hz, 5.6 Hz), 3.6-3.75 (3H, m), 3.8-3.85 (1H, m), 3.9-4.0 (1H,m), 4.15-4.25 (2H, m), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15(2H, m)

Example 853-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)-2-methylphenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-methylpiperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.45 (6H, s), 2.18 (3H, s), 2.29(3H, s), 2.36 (4H, brs), 2.6 (2H, t, J=5.7 Hz), 2.75-2.85 (1H, m),3.25-3.4 (4H, m), 3.55-3.75 (7H, m), 3.82 (1H, d, J=11.8 Hz), 4.17 (2H,t, J=5.7 Hz), 5.0-5.15 (1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.71(1H, d, J=2.5 Hz), 6.87 (1H, d, J=8.4 Hz)

Example 863-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using tris(hydroxymethyl)-aminomethane instead of2-amino-2-methylpropionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.68 (2H, t,J=6.1 Hz), 2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.6-3.75 (9H, m), 3.81(1H, d, J=12.0 Hz), 4.18 (2H, t, J=6.1 Hz), 5.0-5.05 (1H, m), 6.65 (1H,dd, J=8.4 Hz, 2.3 Hz), 6.74 (1H, d, J=2.3 Hz), 6.86 (1H, d, J=8.4 Hz)

Example 873-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using 2-amino-2-methyl-1-propanol instead of2-amino-2-methylpropionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.27 (6H, s), 2.29 (3H, s), 2.58(2H, t, J=6.2 Hz), 2.75-2.85 (1H, m), 3.2-3.4 (4H, m), 3.57 (2H, s),3.6-3.75 (3H, m), 3.82 (1H, d, J=11.9 Hz), 4.16 (2H, t, J=6.2 Hz),4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.0 Hz), 6.72 (1H, d, J=2.0Hz), 6.86 (1H, d, J=8.4 Hz)

Example 883-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1-hydroxy-methyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using 2-amino-2-methyl-1,3-propanediol instead of2-amino-2-methylpropionamide.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.25 (3H, s), 2.29 (3H, s), 2.63(2H, t, J=6.2 Hz), 2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.6-3.7 (7H, m),3.81 (1H, d, J=11.8 Hz), 4.17 (2H, t, J=6.2 Hz), 5.0-5.05 (1H, m), 6.63(1H, dd, J=8.4 Hz, 2.4 Hz), 6.73 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4Hz)

Example 893-(β-D-Glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.45 (6H, s), 2.3 (3H, s),2.35-2.55 (6H, m), 2.6 (2H, t, J=5.7 Hz), 2.75-2.9 (1H, m), 3.25-3.4(4H, m), 3.57 (2H, t, J=5.8 Hz), 3.6-3.8 (7H, m), 3.82 (1H, d, J=11.9Hz), 4.17 (2H, t, J=5.7 Hz), 5.0-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz,2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.87 (1H, d, J=8.4 Hz)

Example 903-(β-D-Glucopyranosyloxy)-4-[(4-{2-[1-(2-hydroxyethyl-carbamoyl)-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 2-aminoethanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.45 (6H, s), 2.29 (3H, s),2.63 (2H, t, J=6.2 Hz), 2.75-2.85 (1H, m), 3.24 (2H, t, J=5.9 Hz),3.3-3.4 (4H, m), 3.51 (2H, t, J=5.9 Hz), 3.6-3.7 (3H, m), 3.82 (1H, d,J=12.0 Hz), 4.18 (2H, t, J=6.2 Hz), 5.0-5.05 (1H, m), 6.64 (1H, dd,J=8.4 Hz, 2.4 Hz), 6.74 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)

Example 913-(β-D-Glucopyranosyloxy)-4-[(4-{2-[1-(3-hydroxypropyl-carbamoyl)-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 3-amino-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.45 (6H, s), 1.55-1.65 (2H,m), 2.29 (3H, s), 2.62 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m), 3.2 (2H, t,J=6.6 Hz), 3.25-3.4 (4H, m), 3.51 (2H, t, J=6.2 Hz), 3.6-3.7 (3H, m),3.82 (1H, d, J=12.0 Hz), 4.18 (2H, t, J=6.1 Hz), 5.0-5.15 (1H, m), 6.64(1H, dd, J=8.4 Hz, 2.3 Hz), 6.73 (1H, d, J=2.3 Hz), 6.87 (1H, d, J=8.4Hz)

Example 924-[(4-{2-[(S)-1-(Carbamoyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using L-alanine amide hydrochloride instead of2-amino-2-methylpropionamide.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.36 (3H, d, J=7.2 Hz), 2.29(3H, s), 2.6-2.85 (3H, m), 3.3-3.4 (4H, m), 3.6-3.7 (3H, m), 3.81 (1H,d, J=12.1 Hz), 4.15-4.25 (2H, m), 4.36 (1H, q, J=7.2 Hz), 5.0-5.05 (1H,m), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.86 (1H,d, J=8.4 Hz)

Example 933-(β-D-Glucopyranosyloxy)-4-[4-{2-[(S)-1-(2-hydroxyethyl-carbamoyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(carboxy)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 2-aminoethanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.34 (3H, d, J=7.2 Hz), 2.29(3H, s), 2.67 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m), 3.2-3.4 (6H, m),3.55 (2H, t, J=5.8 Hz), 3.6-3.7 (3H, m), 3.82 (1H, d, J=12.0 Hz), 4.19(2H, t, J=6.1 Hz), 4.35 (1H, q, J=7.2 Hz), 4.95-5.05 (1H, m), 6.63 (1H,dd, J=8.4 Hz, 2.3 Hz), 6.73 (1H, d, J=2.3 Hz), 6.86 (1H, d, J=8.4 Hz)

Example 944-[(4-{2-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using L-serine amide hydrochloride instead of2-amino-2-methylpropionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 2.29 (3H, s), 2.65-2.9 (3H, m),3.25-3.4 (4H, m), 3.55-3.9 (6H, m), 4.21 (2H, t, J=6.0 Hz), 4.4-4.5 (1H,m), 4.95-5.05 (1H, m), 6.64 (1H, dd, J=8.3 Hz, 2.2 Hz), 6.73 (1H, d,J=2.2 Hz), 6.86 (1H, d, J=8.3 Hz)

Example 953-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1-(hydroxy-methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using 2-amino-1,3-propanediol instead of2-amino-2-methylpropionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.65 (2H, t,J=6.2 Hz), 2.75-2.85 (1H, m), 3.3-3.4 (4H, m), 3.55-3.7 (7H, m), 3.86(1H, d, J=11.6 Hz), 3.9-4.0 (1H, m), 4.19 (2H, t, J=6.2 Hz), 4.95-5.05(1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.72 (1H, d, J=2.4 Hz), 6.86(1H, d, J=8.4 Hz)

Example 963-(β-D-Glucopyranosyloxy)-4-[(4-{2-[(S)-1-(3-hydroxypropyl-carbamoyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(carboxy)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 3-amino-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.34 (3H, d, J=7.2 Hz), 1.6-1.7(2H, m), 2.29 (3H, s), 2.66 (2H, t, J=6.2 Hz), 2.75-2.85 (1H, m),3.2-3.4 (6H, m), 3.54 (2H, t, J=6.2 Hz), 3.6-3.7 (3H, m), 3.82 (1H, d,J=11.6 Hz), 4.19 (2H, t, J=6.2 Hz), 4.32 (1H, q, J=7.2 Hz), 5.0-5.05(1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.86(1H, d, J=8.4 Hz)

Example 973-(β-D-Galactopyranosyloxy)-4-[(4-{4-[1-{[4-(2-hydroxy-ethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]-butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)ethyl-carbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.55-1.65 (4H, m),2.18 (2H, t, J=6.8 Hz), 2.4-2.65 (8H, m), 2.85-2.95 (1H, m), 3.5-3.8(13H, m), 3.85-3.9 (1H, m), 5.08 (1H, d, J=7.8 Hz), 7.04 (2H, d, J=8.0Hz), 7.1 (2H, d, J=8.0 Hz)

Example 983-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(4-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-butyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)ethyl-carbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-methylpiperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methyl-phenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.41 (6H, s), 1.55-1.65 (4H,m), 2.18 (2H, t, J=6.9 Hz), 2.24 (3H, s), 2.35 (4H, brs), 2.57 (2H, t,J=6.6 Hz), 2.85-2.95 (1H, m), 3.45-3.8 (11H, m), 3.85-3.95 (1H, m), 5.08(1H, d, J=7.7 Hz), 7.04 (2H, d, J=7.9 Hz), 7.1 (2H, d, J=7.9 Hz)

Example 993-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-ethoxy)-2-methylphenyl]methyl}-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(40 mg) in N,N-dimethylformamide (1 mL) were added 1-benzylpiperazine(12 mg), 1-hydroxybenzotriazole (8 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16 mg) andtriethylamine (0.023 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=30/1-15/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-{1-[(4-benzylpiperazin-1-yl)-carbonyl]-1-(methyl)ethylcarbamoyl}ethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(31 mg). This material was dissolved in methanol (3 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.02 mL), and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added acetic acid (0.04 mL). The resulting mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give4-{[4-(2-{1-[(4-benzyl-piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(24 mg). This material was dissolved in methanol (3 mL). To the solutionwas added 10% palladium-carbon powder (10 mg), and the mixture wasstirred at room temperature under a hydrogen atmosphere overnight. Theinsoluble material was removed under reduced pressure, and the solventof the filtrate was removed under reduced pressure to give the titlecompound (20 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.45 (6H, s), 2.3 (3H, s),2.5-2.9 (7H, m), 3.25-3.4 (4H, m), 3.45-3.75 (7H, m), 3.81 (1H, d,J=11.5 Hz), 4.17 (2H, t, J=5.7 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd,J=8.4 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.4 Hz)

Example 1003-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(4-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}butyl)-phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{4-[1-carboxy-1-(methyl)ethyl-carbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-oxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.41 (6H, s), 1.5-1.65 (4H, m),2.17 (2H, t, J=7.1 Hz), 2.58 (2H, t, J=6.8 Hz), 2.72 (4H, brs),2.85-2.95 (1H, m), 3.45-3.8 (11H, m), 3.8-3.9 (1H, m), 5.08 (1H, d,J=7.7 Hz), 7.04 (2H, d, J=8.0 Hz), 7.1 (2H, d, J=8.0 Hz)

Example 1014-[(4-{2-[(S)-5-Amino-1-(carbamoyl)pentylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methyl-phenyl]methyl}-5-isopropyl-1H-pyrazoleand (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide hydrochlorideinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.3-1.95 (6H, m), 2.3 (3H, s),2.6-2.9 (5H, m), 3.3-3.4 (4H, m), 3.6-3.7 (3H, m), 3.82 (1H, d, J=11.8Hz), 4.15-4.25 (2H, m), 4.38 (1H, dd, J=9.3 Hz, 4.8 Hz), 5.0-5.05 (1H,m), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.86 (1H,d, J=8.4 Hz)

Example 1024-[(4-{2-[(S)-5-Amino-5-(carbamoyl)pentylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methyl-phenyl]methyl}-5-isopropyl-1H-pyrazoleand (S)-6-amino-2-(benzyloxycarbonylamino)hexanamide hydrochlorideinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.3-1.8 (6H, m), 2.29 (3H, s),2.59 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m), 3.21 (2H, t, J=6.9 Hz),3.3-3.4 (5H, m), 3.6-3.7 (3H, m), 3.81 (1H, d, J=11.5 Hz), 4.18 (2H, t,J=6.1 Hz), 5.0-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H,d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)

Example 1033-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propyl)-2-methylphenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(benzyloxycarbonyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.16 (2H, t, J=7.2 Hz), 2.3 (3H, s), 2.55 (2H, t, J=7.5 Hz), 2.65-2.9(5H, m), 3.2-3.45 (4H, m), 3.5-3.9 (8H, m), 4.95-5.05 (1H, m), 6.8-6.9(2H, m), 6.9-7.0 (1H, m)

Example 1044-{[4-(3-{1-[(S)-5-Amino-5-(carbamoyl)pentylcarbamoyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand (S)-6-amino-2-(benzyloxycarbonylamino)hexanamide hydro-chlorideinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzylpiperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.2-1.6 (11H, m), 1.6-1.75 (1H,m), 1.8-1.9 (2H, m), 2.19 (2H, t, J=7.8 Hz), 2.58 (2H, t, J=7.7 Hz),2.85-2.95 (1H, m), 3.1-3.25 (2H, m), 3.25-3.35 (1H, m), 3.52 (1H, dd,J=9.7 Hz, 3.4 Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m), 3.86 (1H, d,J=3.1 Hz), 5.08 (1H, d, J=8.0 Hz), 7.0-7.15 (4H, m)

Example 1053-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole

To a solution of4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.12 g) in N,N-dimethylformamide (3 mL) were added1-(benzyloxycarbonyl)piperazine (43 mg), 1-hydroxybenzo-triazole (19mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (50mg) and triethylamine (0.027 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water. Theprecipitated crystals were collected by filtration, and washed withwater and dried under reduced pressure to give4-[(4-{3-[1-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.14 g). This material was dissolved in ethanol (4 mL). To the solutionwas added 10% palladium-carbon powder (30 mg), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 1.5 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent:dichloromethane/methanol=10/1-5/1) to give5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}propoxy)-2-methyl-phenyl]methyl}-3-(2,3,4,6-tetra-O-pivaloyl-β-D-gluco-pyranosyloxy)-1H-pyrazole(89 mg). This material was dissolved in methanol (6 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.087 mL), and themixture was stirred at 50° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (54 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.95-2.05 (2H,m), 2.29 (3H, s), 2.39 (2H, t, J=7.3 Hz), 2.55-2.9 (5H, m), 3.25-3.4(4H, m), 3.5-3.7 (7H, m), 3.75-3.85 (1H, m), 3.95 (2H, t, J=6.0 Hz),5.0-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.3 Hz), 6.71 (1H, d, J=2.3Hz), 6.84 (1H, d, J=8.4 Hz)

Example 1063-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(40 mg) in N,N-dimethylformamide (2 mL) were added1-(2-hydroxyethyl)piperazine (7 mg), 1-hydroxybenzotriazole (7 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg) andtriethylamine (0.018 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloro-methane/methanol=15/1) to give4-[(4-{3-[1-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(27 mg). This material was dissolved in methanol (2 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.015 mL), and themixture was stirred at 50° C. overnight. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (12 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.95-2.05 (2H,m), 2.29 (3H, s), 2.35-2.5 (8H, m), 2.75-2.85 (1H, m), 3.25-3.4 (4H, m),3.55-3.75 (9H, m), 3.75-3.85 (1H, m), 3.94 (2H, t, J=6.1 Hz), 5.0-5.05(1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.7 (1H, d, J=2.4 Hz), 6.85(1H, d, J=8.4 Hz)

Example 1073-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 106 using 1-methylpiperazine instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.95-2.05 (2H,m), 2.22 (3H, s), 2.25-2.45 (9H, m), 2.75-2.85 (1H, m), 3.25-3.4 (4H,m), 3.55-3.75 (7H, m), 3.75-3.85 (1H, m), 3.95 (2H, t, J=6.0 Hz), 5.03(1H, d, J=7.5 Hz), 6.61 (1H, dd, J=8.3 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6Hz), 6.85 (1H, d, J=8.3 Hz)

Example 1083-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethyl-carbamoyl)-1-(methyl)ethylcarbamoyl]propoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 106 using 2-aminoethanol instead of1-(2-hydroxyethyl)piperazine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.95-2.05 (2H,m), 2.28 (3H, s), 2.39 (2H, t, J=7.4 Hz), 2.75-2.85 (1H, m), 3.2-3.4(6H, m), 3.56 (2H, t, J=5.9 Hz), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m),3.94 (2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.3Hz), 6.71 (1H, d, J=2.3 Hz), 6.85 (1H, d, J=8.4 Hz)

Reference Example 541-(3-Benzoyloxypropyl)-1,2-dihydro-4-[(4-iodophenyl)-methyl]-5-isopropyl-3H-pyrazol-3-one

To a solution of1,2-dihydro-4-[(4-iodophenyl)-methyl]-5-isopropyl-3H-pyrazol-3-one (5 g)and imidazole (1.19 g) in N,N-dimethylformamide (20 mL) was addedtriisopropylsilyl chloride (3.1 g) at room temperature, and the mixturewas stirred for 3 hours. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure to give4-[(4-iodophenyl)methyl]-5-isopropyl-3-triiso-propylsilyloxy-1H-pyrazole(7.27 g). To a solution of obtained4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyl-oxy-1H-pyrazole(3 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (55%,0.33 g) under ice-cooling, and the mixture was stirred for 20 minutes.To the reaction mixture were added a solution of1-benzoyloxy-3-chloropropane (3.0 g) in N,N-dimethylformamide (10 mL)and potassium iodide (0.25 g) at the same temperature, and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas poured into water, and the mixture was extracted with ethyl acetate.The extract was washed with water and brine, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=20/1-10/1) to give1-(3-benzoyloxypropyl)-4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole(2.55 g). This material was dissolved in tetrahydrofuran (3 mL). To thesolution was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 10mL), and the mixture was stirred at room temperature overnight. Thereaction mixture was diluted with ethyl acetate, and the resultingmixture was poured into water. The organic layer was separated, and theorganic layer was washed with brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure. To the residuewas added a mixed solvent of n-hexane and ethyl acetate (20/1) (10 mL),and the mixture was stirred at room temperature for 1 hour. Theprecipitated crystals were collected by filtration, and washed with amixed solvent of n-hexane and ethyl acetate (20/1) and dried underreduced pressure to give the title compound (0.85 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.06 (6H, d, J=7.3 Hz), 2.1-2.2 (2H, m),2.95-3.1 (1H, m), 3.6 (2H, s), 4.02 (2H, t, J=6.9 Hz), 4.27 (2H, t,J=6.1 Hz), 6.94 (2H, d, J=8.3 Hz), 7.5-7.7 (5H, m), 7.9-8.0 (2H, m),9.51 (1H, s)

Reference Example 55 Benzyl 2-amino-2-methylpropionate

Benzyl 2-amino-2-methylpropionate hydrochloride (1.48 g) was dissolvedin ethyl acetate (60 mL) and a saturated aqueous sodium hydrogencarbonate solution (20 mL), and the organic layer was separated. Theorganic layer was washed with brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure to give thetitle compound (1.2 g).

¹H-NMR (CDCl₃) δ ppm: 1.37 (6H, s), 5.14 (2H, s), 7.3-7.45 (5H, m)

Reference Example 563-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-1-(3-benzoyloxypropyl)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

To a mixture of1-(3-benzoyloxypropyl)-1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one(0.85 g), acetobromo-α-D-galactose (0.91 g) andbenzyltri(n-butyl)-ammonium chloride (0.53 g) in dichloromethane (2.55mL) was added 5 mol/L aqueous sodium hydroxide solution (0.85 mL), andthe mixture was stirred at room temperature for 6 hours. The reactionmixture was diluted with dichloromethane, and the mixture was pouredinto water. The organic layer was separated, and washed with brine anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure. To a solution of the residue in acetonitrile (2.5 mL)were added 3-butenoic acid (0.36 g), triethylamine (1.71 g), palladiumacetate (II) (38 mg) and tris(2-methylphenyl)phosphine (0.1 g), and themixture was refluxed for 3 hours. The solvent was removed under reducedpressure, and the residue was dissolved in ethyl acetate. The solutionwas washed with water. The aqueous layer was extracted with ethylacetate. The combined organic layers were washed with water and brine,and dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was dissolved in tetrahydrofuran (5mL). To the solution were added benzyl 2-amino-2-methylpropionate (1.63g), 1-hydroxybenzotriazole (0.46 g) and1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (0.65 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was poured into water, and the resulting mixture was extractedwith ethyl acetate. The extract was washed with water and brine, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=1/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-1-(3-benzoyloxypropyl)-4-[(4-{(1E)-3-[1-carboxy-1-(methyl)ethylcarbamoyl]prop-1-enyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(0.55 g). This material was dissolved in methanol (5 mL). To thesolution was added 10% palladium-carbon powder (0.15 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 3 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(0.48 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.53 (3H, s), 1.54 (3H, s),1.85-2.2 (16H, m), 2.25-2.35 (2H, m), 2.61 (2H, t, J=7.1 Hz), 2.95-3.05(1H, m), 3.67 (1H, d, J=16.7 Hz), 3.71 (1H, d, J=16.7 Hz), 3.95-4.05(1H, m), 4.05-4.2 (4H, m), 4.36 (2H, t, J=5.7 Hz), 5.0-5.1 (1H, m),5.3-5.45 (2H, m), 5.51 (1H, d, J=8.2 Hz), 6.19 (1H, s), 6.95-7.05 (4H,m), 7.4-7.5 (2H, m), 7.5-7.6 (1H, m), 8.0-8.1 (2H, m)

Example 1093-(β-D-Galactopyranosyloxy)-1-(3-hydroxypropyl)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-1-(3-benzoyloxypropyl)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(benzyloxycarbonyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.42 (6H, s), 1.8-2.0 (4H, m),2.17 (2H, t, J=7.7 Hz), 2.58 (2H, t, J=7.4 Hz), 2.65-2.8 (4H, m),3.05-3.2 (1H, m), 3.45-3.9 (14H, m), 4.08 (2H, t, J=7.0 Hz), 5.11 (1H,d, J=7.8 Hz), 7.0-7.15 (4H, m)

Example 1103-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(37 g) was dissolved in N,N-dimethylformamide (180 mL). To the solutionwere added 1-(benzyloxycarbonyl)piperazine (28.4 g),1-hydroxybenzo-triazole (10.5 g) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (14.8 g),and the mixture was stirred at room temperature overnight. The reactionmixture was poured into water, and the resulting mixture was extractedwith ethyl acetate twice. The extracts were washed with water and brine,and dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=1/2-ethyl acetate) to givethe title compound (40.5 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.56 (6H, s), 1.85-1.95 (5H, m),1.98 (3H, s), 2.02 (3H, s), 2.12 (2H, t, J=7.5 Hz), 2.16 (3H, s), 2.58(2H, t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.4-3.55 (4H, m), 3.55-3.75 (6H,m), 4.0-4.1 (1H, m), 4.1-4.2 (2H, m), 5.09 (1H, dd, J=10.6 Hz, 3.3 Hz),5.14 (2H, s), 5.35-5.45 (2H, m), 5.56 (1H, d, J=7.8 Hz), 6.39 (1H, s),6.95-7.1 (4H, m), 7.3-7.4 (5H, m)

Example 1114-[(4-{3-[1-{[4-(Benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyloxy)-4-[(4-{3-[1-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole(39.5 g) in methanol (160 mL) was added sodium methoxide (28% methanolsolution, 8.24 mL), and the mixture was stirred at room temperatureovernight. To the reaction mixture was added acetic acid (2.7 mL), andthe resulting mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give the title compound (21.3 g).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.8-1.9 (2H, m),2.16 (2H, t, J=7.8 Hz), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m),3.35-3.8 (15H, m), 3.85-3.9 (1H, m), 5.07 (1H, d, J=7.9 Hz), 5.12 (2H,s), 7.04 (2H, d, J=8.2 Hz), 7.11 (2H, d, J=8.2 Hz), 7.25-7.4 (5H, m)

Reference Example 57[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methanol

To a solution of tetrahydro-4H-pyran-4-ol (3.62 g) and triethylamine(5.6 mL) in tetrahydrofuran (35 mL) was added methanesulfonyl chloride(2.93 mL) under ice-cooling, and the mixture was stirred at roomtemperature for 1 hour. The insoluble material was removed byfiltration. To the filtrate were added N,N-dimethylformamide (70 mL),4-benzyloxy-2-hydroxybenz-aldehyde (5.39 g) and cesium carbonate (23 g),and the mixture was stirred at 80° C. for 12 hours. The reaction mixturewas poured into water, and the resulting mixture was extracted withdiethyl ether. The extract was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give4-benzyloxy-2-(tetrahydro-4H-pyran-4-yl-oxy)benzaldehyde (4.58 g). Thismaterial was dissolved in ethanol (70 mL). To the solution was addedsodium borohydride (0.28 g) under ice-cooling, and the mixture wasstirred at room temperature for 3 hours. To the reaction mixture wasadded methanol, and the resulting mixture was concentrated under reducedpressure. A saturated aqueous sodium hydrogen carbonate solution wasadded to the residue, and the mixture was extracted with diethyl ether.The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine successively, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give the titlecompound (4.45 g).

¹H-NMR (CDCl₃) δ ppm: 1.75-1.85 (2H, m), 1.95-2.05 (2H, m), 2.11 (1H, t,J=6.3 Hz), 3.5-3.65 (2H, m), 3.9-4.0 (2H, m), 4.45-4.55 (1H, m), 4.63(2H, d, J=6.3 Hz), 5.05 (2H, s), 6.5-6.6 (2H, m), 7.19 (1H, d, J=7.7Hz), 7.3-7.45 (5H, m)

Reference Example 584-{[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methanol (4.45 g) intetrahydrofuran (28 mL) were added triethylamine (2.27 mL) andmethanesulfonyl chloride (1.21 mL) under ice-cooling, and the mixturewas stirred for 1 hour. The insoluble material was removed byfiltration. The obtained solution of[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)-phenyl]methyl mesylate intetrahydrofuran was added to a suspension of sodium hydride (55%, 710mg) and methyl 4-methyl-3-oxopentanoate (2.25 g) in tetrahydrofuran (56mL), and the mixture was heated for reflux for 8 hours. To the reactionmixture was added 1 mol/L hydrochloric acid, and the resulting mixturewas extracted with diethyl ether. The organic layer was washed withwater, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure. To a solution of the residue in toluene(8 mL) was added hydrazine monohydrate (3.43 mL), and the mixture wasstirred at 100° C. for 8 hours. The reaction mixture was purified bycolumn chromatography on silica gel (eluent:dichloromethane/methanol=20/1-10/1) to give the title compound (1.69 g).

¹H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=7.1 Hz), 1.75-1.9 (2H, m), 1.95-2.1(2H, m), 2.9-3.05 (1H, m), 3.5-3.6 (2H, m), 3.64 (2H, s), 3.9-4.05 (2H,m), 4.4-4.5 (1H, m), 5.0 (2H, s), 6.45-6.55 (2H, m), 7.0 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Reference Example 593-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-galactose instead of4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.2 (6H, m), 1.78 (3H, s), 1.98 (3H, s), 2.03(3H, s), 2.16 (3H, s), 2.28 (3H, s), 2.75-2.85 (1H, m), 3.51 (1H, d,J=16.4 Hz), 3.62 (1H, d, J=16.4 Hz), 4.0-4.1 (1H, m), 4.1-4.2 (2H, m),5.02 (2H, s), 5.07 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.51(1H, d, J=7.9 Hz), 6.66 (1H, dd, J=8.3 Hz, 2.8 Hz), 6.75-6.85 (2H, m),7.2-7.45 (5H, m)

Reference Example 604-{[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide instead of4-{[4-(2-benzyloxy-carbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.7-1.85 (2H, m), 1.95-2.05 (2H,m), 2.85-2.95 (1H, m), 3.5-3.65 (4H, m), 3.8-3.9 (1H, m), 3.9-4.0 (2H,m), 4.12 (1H, dd, J=12.4 Hz, 5.1 Hz), 4.19 (1H, dd, J=12.4 Hz, 1.8 Hz),4.4-4.5 (1H, m), 4.99 (2H, s), 5.15-5.3 (2H, m), 5.36 (1H, t, J=9.4 Hz),5.66 (1H, d, J=8.0 Hz), 6.42 (1H, dd, J=8.3 Hz, 2.3 Hz), 6.47 (1H, d,J=2.3 Hz), 6.86 (1H, d, J=8.3 Hz), 7.25-7.45 (5H, m)

Reference Example 613-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 25 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-benzyloxy-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.83 (3H, s), 1.98 (3H, s), 2.03(3H, s), 2.16 (3H, s), 2.25 (3H, s), 2.75-2.9 (1H, m), 3.5 (1H, d,J=16.6 Hz), 3.6 (1H, d, J=16.6 Hz), 4.0-4.05 (1H, m), 4.1-4.2 (2H, m),4.78 (1H, brs), 5.06 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.5(1H, d, J=8.2 Hz), 6.52 (1H, dd, J=8.1 Hz, 2.6 Hz), 6.62 (1H, d, J=2.6Hz), 6.76 (1H, d, J=8.1 Hz)

Reference Example 624-{[4-Hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-gluco-pyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 25 using4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.9 (2H, m), 1.95-2.1 (2H,m), 2.8-2.95 (1H, m), 3.52 (1H, d, J=16.5 Hz), 3.55-3.65 (3H, m),3.8-3.9 (1H, m), 3.9-4.05 (2H, m), 4.05-4.2 (2H, m), 4.4-4.5 (1H, m),5.14 (1H, brs), 5.15-5.3 (2H, m), 5.3-5.4 (1H, m), 5.65 (1H, d, J=8.1Hz), 6.22 (1H, dd, J=8.2 Hz, 2.3 Hz), 6.37 (1H, d, J=2.3 Hz), 6.78 (1H,d, J=8.2 Hz)

Reference Example 633-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[3-(benzyloxycarbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 27 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.81 (3H, s), 1.98 (3H, s),2.02 (3H, s), 2.05-2.15 (2H, m), 2.16 (3H, s), 2.26 (3H, s), 2.56 (2H,t, J=7.1 Hz), 2.7-2.85 (1H, m), 3.5 (1H, d, J=16.5 Hz), 3.6 (1H, d,J=16.5 Hz), 3.9-4.0 (2H, m), 4.0-4.1 (1H, m), 4.1-4.2 (2H, m), 5.07 (1H,dd, J=10.6 Hz, 3.6 Hz), 5.13 (2H, s), 5.35-5.45 (2H, m), 5.52 (1H, d,J=8.2 Hz), 6.55 (1H, dd, J=8.6 Hz, 2.5 Hz), 6.66 (1H, d, J=2.5 Hz), 6.79(1H, d, J=8.6 Hz), 7.25-7.4 (5H, m)

Reference Example 644-({4-[3-(Benzyloxycarbonyl)propoxy]-2-(tetrahydro-4H-pyran-4-yloxy)phenyl}methyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 27 using4-{[4-hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.85 (2H, m), 1.95-2.15(4H, m), 2.56 (2H, t, J=7.3 Hz), 2.8-2.95 (1H, m), 3.5-3.65 (4H, m),3.8-3.9 (1H, m), 3.9-4.05 (4H, m), 4.05-4.25 (2H, m), 4.4-4.5 (1H, m),5.13 (2H, s), 5.15-5.3 (2H, m), 5.36 (1H, t, J=9.5 Hz), 5.66 (1H, d,J=8.1 Hz), 6.3 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.38 (1H, d, J=2.5 Hz), 6.84(1H, d, J=8.4 Hz), 7.25-7.4 (5H, m)

Reference Example 653-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-carboxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 25 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[3-(benzyloxy-carbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.78 (3H, s), 1.98 (3H, s),2.02 (3H, s), 2.05-2.15 (2H, m), 2.16 (3H, s), 2.27 (3H, s), 2.45-2.6(2H, m), 2.75-2.85 (1H, m), 3.49 (1H, d, J=16.8 Hz), 3.6 (1H, d, J=16.8Hz), 3.98 (2H, t, J=6.3 Hz), 4.0-4.1 (1H, m), 4.1-4.25 (2H, m), 5.06(1H, dd, J=10.3 Hz, 3.4 Hz), 5.3-5.45 (3H, m), 6.58 (1H, dd, J=8.6 Hz,2.4 Hz), 6.68 (1H, d, J=2.4 Hz), 6.78 (1H, d, J=8.6 Hz)

Reference Example 664-{[4-(3-Carboxypropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)-phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 25 using4-({4-[3-(benzyl-oxycarbonyl)propoxy]-2-(tetrahydro-4H-pyran-4-yloxy)-phenyl}methyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.9 (2H, m), 1.95-2.15 (4H,m), 2.5-2.6 (2H, m), 2.8-2.95 (1H, m), 3.45-3.65 (4H, m), 3.8-3.9 (1H,m), 3.9-4.05 (4H, m), 4.1-4.25 (2H, m), 4.4-4.55 (1H, m), 5.2-5.3 (2H,m), 5.36 (1H, t, J=9.2 Hz), 5.52 (1H, d, J=7.7 Hz), 6.33 (1H, dd, J=8.1Hz, 2.1 Hz), 6.41 (1H, d, J=2.1 Hz), 6.84 (1H, d, J=8.1 Hz)

Reference Example 673-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 45 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-carboxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.53 (6H, s), 1.83 (3H, s),1.95-2.1 (8H, m), 2.15 (3H, s), 2.26 (3H, s), 2.34 (2H, t, J=7.2 Hz),2.7-2.85 (1H, m), 3.5 (1H, d, J=16.6 Hz), 3.6 (1H, d, J=16.6 Hz),3.85-3.95 (2H, m), 4.0-4.1 (1H, m), 4.1-4.2 (2H, m), 5.07 (1H, dd,J=10.4 Hz, 3.5 Hz), 5.15 (2H, s), 5.35-5.45 (2H, m), 5.52 (1H, d, J=8.1Hz), 6.06 (1H, s), 6.55 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.66 (1H, d, J=2.6Hz), 6.79 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)

Reference Example 684-{[4-{3-[1-Benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]-propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 45 using4-{[4-(3-carboxy-propoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methyl-phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.54 (6H, s), 1.75-1.85 (2H, m),2.0-2.1 (4H, m), 2.34 (2H, t, J=7.2 Hz), 2.8-2.95 (1H, m), 3.5-3.65 (4H,m), 3.8-4.05 (5H, m), 4.05-4.25 (2H, m), 4.4-4.5 (1H, m), 5.1-5.3 (4H,m), 5.36 (1H, t, J=9.5 Hz), 5.65 (1H, d, J=7.5 Hz), 6.09 (1H, brs), 6.29(1H, dd, J=8.3 Hz, 2.2 Hz), 6.4 (1H, d, J=2.2 Hz), 6.83 (1H, d, J=8.3Hz), 7.25-7.4 (5H, m)

Reference Example 693-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 48 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-benzyloxy-carbonyl-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-benzyloxy-carbonyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.55 (3H, s), 1.56 (3H, s),1.79 (3H, s), 1.98 (3H, s), 2.0-2.2 (8H, m), 2.26 (3H, s), 2.4 (2H, t,J=6.9 Hz), 2.7-2.85 (1H, m), 3.49 (1H, d, J=16.6 Hz), 3.59 (1H, d,J=16.6 Hz), 3.98 (2H, t, J=6.1 Hz), 4.0-4.2 (2H, m), 4.22 (1H, dd,J=10.9 Hz, 5.7 Hz), 5.0-5.1 (1H, m), 5.3-5.45 (3H, m), 6.24 (1H, s),6.59 (1H, dd, J=8.2 Hz, 2.7 Hz), 6.69 (1H, d, J=2.7 Hz), 6.75 (1H, d,J=8.2 Hz)

Reference Example 704-{[4-{3-[1-Carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 48 using4-{[4-{3-[1-benzyl-oxycarbonyl-1-(methyl)ethylcarbamoyl]propoxy}-2-(tetra-hydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.54 (6H, s), 1.7-1.9 (2H, m),1.95-2.15 (4H, m), 2.35-2.45 (2H, m), 2.8-2.95 (1H, m), 3.45-3.65 (4H,m), 3.8-3.9 (1H, m), 3.9-4.05 (4H, m), 4.05-4.25 (2H, m), 4.4-4.55 (1H,m), 5.15-5.3 (2H, m), 5.36 (1H, t, J=9.4 Hz), 5.56 (1H, d, J=8.4 Hz),6.17 (1H, brs), 6.32 (1H, d, J=8.1 Hz), 6.41 (1H, s), 6.82 (1H, d, J=8.1Hz)

Example 1123-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(benzyloxycarbonyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.95-2.05 (2H, m),2.29 (3H, s), 2.39 (2H, t, J=7.4 Hz), 2.55-2.9 (5H, m), 3.45-3.8 (11H,m), 3.85 (1H, d, J=3.2 Hz), 3.95 (2H, t, J=6.1 Hz), 5.04 (1H, d, J=7.5Hz), 6.61 (1H, dd, J=8.2 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.84 (1H,d, J=8.2 Hz)

Example 1133-(β-D-Galactopyranosyloxy)-5-isopropyl-4-[(4-{3-[1-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 78 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.42 (6H, s), 1.95-2.05 (2H,m), 2.28 (3H, s), 2.3-2.55 (8H, m), 2.7-2.85 (1H, m), 3.45-3.8 (13H, m),3.85 (1H, d, J=2.9 Hz), 3.94 (2H, t, J=6.0 Hz), 5.04 (1H, d, J=7.6 Hz),6.6 (1H, d, J=8.5 Hz), 6.7 (1H, s), 6.85 (1H, d, J=8.5 Hz)

Example 1143-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)ethylcarbamoyl}-propoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 105 using4-{[4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.42 (6H, s), 1.7-1.85 (2H, m),1.95-2.1 (4H, m), 2.38 (2H, t, J=7.4 Hz), 2.6-2.8 (4H, m), 2.8-2.95 (1H,m), 3.25-3.45 (4H, m), 3.5-3.75 (9H, m), 3.83 (1H, d, J=12.1 Hz),3.9-4.0 (4H, m), 4.5-4.65 (1H, m), 5.07 (1H, d, J=7.1 Hz), 6.4 (1H, dd,J=8.3 Hz, 2.5 Hz), 6.54 (1H, d, J=2.5 Hz), 6.89 (1H, d, J=8.3 Hz)

Reference Example 714-[(4-Bromo-2-fluorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 2 using 4-bromo-2-fluoro-benzyl bromide instead of4-bromobenzyl bromide.

¹H-NMR (CDCl₃) δ ppm: 1.17 (6H, d, J=7.1 Hz), 2.85-3.05 (1H, m), 3.67(2H, s), 7.0-7.3 (3H, m)

Reference Example 723-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-bromo-2-fluorophenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-[(4-bromo-2-fluorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-galactose instead of4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.15-1.25 (6H, m), 1.92 (3H, s), 1.99 (3H, s),2.02 (3H, s), 2.18 (3H, s), 2.9-3.0 (1H, m), 3.59 (1H, d, J=16.1 Hz),3.67 (1H, d, J=16.1 Hz), 4.05-4.25 (3H, m), 5.1 (1H, dd, J=10.4 Hz, 3.4Hz), 5.35-5.45 (2H, m), 5.58 (1H, d, J=8.1 Hz), 6.95-7.05 (1H, m),7.1-7.2 (2H, m)

Reference Example 733-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-fluorophenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 4 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-bromo-2-fluoro-phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.89 (3H, s), 1.99 (3H, s), 2.01(3H, s), 2.17 (3H, s), 2.85-3.0 (1H, m), 3.27 (2H, d, J=6.9 Hz), 3.59(1H, d, J=16.2 Hz), 3.7 (1H, d, J=16.2 Hz), 4.05-4.3 (3H, m), 5.1 (1H,dd, J=10.2 Hz, 3.5 Hz), 5.3-5.5 (3H, m), 6.2-6.35 (1H, m), 6.43 (1H, d,J=16.2 Hz), 6.9-7.15 (3H, m)

Reference Example 741-(2-Amino-2-methylpropionyl)-4-(benzyloxycarbonyl)-piperazine

To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propionic acid(10 g) in tetrahydrofuran (20 mL) were added1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzo-triazole (8.02g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride(11.4 g), and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure. The residue was dissolved in a mixed solvent ofn-hexane and ethyl acetate (1/1) (40 mL) at 60° C. with heating, and thesolution was stirred at room temperature overnight. To the mixture wasadded the same solvent (30 mL), and the mixture was further stirredovernight. The precipitated crystals were collected by filtration, andwashed with the same solvent and dried under reduced pressure to give4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine(13.5 g). To a solution of the obtained4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]-piperazine(5 g) in tetrahydrofuran (30 mL) was added hydrochloric acid (4 mol/L1,4-dioxane solution, 40 mL), and the mixture was stirred at roomtemperature overnight. The precipitated crystals were collected byfiltration. The obtained crystals were dissolved in ethyl acetate and asaturated aqueous sodium hydrogen carbonate solution. The organic layerwas separated, and the organic layer was washed with brine and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure to give the title compound (3.65 g).

¹H-NMR (CDCl₃) δ ppm: 1.41 (6H, s), 3.45-3.55 (4H, m), 3.7-3.95 (4H,br), 5.15 (2H, s), 7.25-7.4 (5H, m)

Example 1154-{[2-Fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-galacto-pyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-fluorophenyl}methyl)-5-isopropyl-1H-pyrazoleand 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazineinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m),2.17 (2H, t, J=7.6 Hz), 2.6 (2H, t, J=7.6 Hz), 2.7-2.85 (4H, m),2.85-3.0 (1H, m), 3.45-3.85 (11H, m), 3.85-3.9 (1H, m), 5.09 (1H, d,J=7.8 Hz), 6.8-6.9 (2H, m), 7.0-7.15 (1H, m)

Reference Example 75 4-Bromo-2-chlorobenzyl alcohol

The title compound was prepared in a similar manner to that described inReference Example 14 using 4-bromo-2-chloro-benzoic acid instead of4-bromo-2-methylbenzoic acid.

¹H-NMR (CDCl₃) δ ppm: 1.9-2.0 (1H, m), 4.73 (2H, d, J=5.5 Hz), 7.3-7.45(2H, m), 7.45-7.55 (1H, m)

Reference Example 764-[(4-Bromo-2-chlorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 15 using 4-bromo-2-chloro-benzyl alcohol instead of4-bromo-2-methylbenzyl alcohol.

¹H-NMR (DMSO-d₆) δ ppm: 1.07 (6H, d, J=6.9 Hz), 2.7-2.85 (1H, m), 3.61(2H, s), 6.97 (1H, d, J=8.5 Hz), 7.46 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.66(1H, d, J=2.0 Hz)

Reference Example 773-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-chlorophenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 12 using4-[(4-bromo-2-chlorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)-phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.17 (6H, d, J=7.0 Hz), 1.9 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.07 (3H, s), 2.85-3.0 (1H, m), 3.65 (1H, d, J=16.7 Hz),3.74 (1H, d, J=16.7 Hz), 3.8-3.9 (1H, m), 4.05-4.2 (1H, m), 4.31 (1H,dd, J=12.8 Hz, 4.3 Hz), 5.1-5.35 (3H, m), 5.6 (1H, d, J=8.1 Hz), 6.93(1H, d, J=8.2 Hz), 7.24 (1H, dd, J=8.2 Hz, 1.8 Hz), 7.49 (1H, d, J=1.8Hz)

Reference Example 783-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 4 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-chloro-phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)-methyl]-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.85 (3H, s), 2.0 (3H, s), 2.02(3H, s), 2.05 (3H, s), 2.85-3.0 (1H, m), 3.27 (2H, d, J=6.4 Hz), 3.68(1H, d, J=16.7 Hz), 3.78 (1H, d, J=16.7 Hz), 3.8-3.9 (1H, m), 4.1-4.2(1H, m), 4.32 (1H, dd, J=12.6 Hz, 3.8 Hz), 5.15-5.3 (3H, m), 5.43 (1H,d, J=7.8 Hz), 6.2-6.35 (1H, m), 6.42 (1H, d, J=16.1 Hz), 6.96 (1H, d,J=1.6 Hz), 7.13 (1H, dd, J=8.2 Hz, 1.6 Hz), 7.36 (1H, d, J=1.6 Hz)

Example 1164-{[2-Chloro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-3-(β-D-glucopyranosyl-oxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 99 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazoleand 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazineinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazoleand 1-benzyl-piperazine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.43 (6H, s), 1.8-1.95 (2H, m),2.17 (2H, t, J=7.7 Hz), 2.59 (2H, t, J=7.6 Hz), 2.65-2.95 (5H, m),3.25-3.45 (4H, m), 3.5-3.9 (8H, m), 5.09 (1H, d, J=7.1 Hz), 6.95-7.1(2H, m), 7.2 (1H, d, J=1.3 Hz)

Test Example 1 Assay for Inhibitory Effects on Human SGLT1 Activity

1) Cloning and Construction of the Vector Expressing Human SGLT1

The cDNA library was prepared for PCR amplification by reversetranscription from total RNA deprived from human small intestine (Origene) using oligo-dT as a primer. Using this cDNA library as a template,the DNA fragment coding 1 to 2005 bp of human SGLT1 (ACCESSION: M24847),which was reported by Hediger et al., was amplified by PCR method andinserted into the multi-cloning site of pcDNA3.1(−) (Invitrogen). TheDNA sequence inserted was perfectly matched to the previously reportedsequence.

2) Establishment of Cell Line Stably Expressing Human SGLT1

The expression vector of human SGLT1 was digested by Sca I into a linearDNA. The linear DNA was transfected into CHO-K1 cells by means oflipofection (Effectene Transfection Reagent: QIAGEN). Neomycin resistantcell lines were selected by culture in the medium containing G418 (1mg/mL, LIFE TECHNOLOGIES), and then the activity against the uptake ofmethyl-α-D-gluco-pyranoside was measured by the method described below.The cell line, which showed the greatest uptake activity, was selectedand designated as CS1-5-11D. CS1-5-11D cells were cultured in thepresence of G418 at 200 μg/mL.

3) Measurement of the Inhibitory Activity Against the Uptake ofmethyl-α-D-glucopyranoside (α-MG)

CS1-5-11D cells were seeded into a 96-well culture plate at a density of3×10⁴ cells/well and cultured for 2 days, and were used in the uptakeassay. A mixture of non-labeled (Sigma) and ¹⁴C-labeled α-MG (AmershamPharmcia Biotec) was added to the uptake buffer (pH 7.4; containing 140mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mMmagnesium chloride, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, and 5 mM tris(hydroxymethyl)aminomethane) at the finalconcentration of 1 mM. A test compound was dissolved in dimethylsulfoxide, and then appropriately diluted with distilled water. The testcompound solution was added to the uptake buffer containing 1 mM α-MG,and designated as a measurement buffer. For the control group, themeasurement buffer without any test compound was prepared. For measuringthe basal uptake, a basal uptake measurement buffer which contains 140mM chorine chloride instead of sodium chloride was prepared. Afterremoving the culture medium of CS1-5-11D cells, 180 μL of thepre-treatment buffer (the basal uptake buffer without α-MG) was added toeach well and incubated at 37° C. for 10 minutes. After repeating thesame treatment, the pre-treatment buffer was removed. To each well wasadded 75 μL of the measurement buffer or the basal uptake buffer wasadded and incubated at 37° C. for 1 hour. After removing the measurementbuffer, cells were washed twice with 180 μL per well of the washingbuffer (the basal uptake buffer containing 10 mM non-labeled α-MG). Thecells were solubilized by 75 μL per well of 0.2 mol/L sodium hydroxide.The cell lysates were transferred into PicoPlates (Packard), and thenadded 150 μL of MicroScint-40 (Packard) and mixed. Radioactivity wasmeasured by means of micro-scintillation counter TopCount (Packard). Onehundred % was set to the difference between the uptake in the controlgroup and the basal uptake, and the uptake of methylα-D-gluco-pyranoside at each drug concentration were calculated. Thedrug concentration, at which 50% uptake of methyl α-D-glucopyranosidewas inhibited (IC₅₀ value), was calculated using logit plot.

The results are shown in Table 1.

TABLE 1 Test compound IC₅₀ value (nM) Example 15 113 Example 18 181Example 21 12 Example 24 24 Example 27 237 Example 28 267 Example 29 431Example 30 52 Example 31 96 Example 32 220 Example 33 174 Example 34 245Example 35 115 Example 48 31 Example 57 39 Example 61 18

Test Example 2 Assay for Inhibitory Effects on Blood Glucose LevelIncrease in rats

1) Preparation of Diabetic Rat Model

Male wistar rats (Japan Charles River), aged 8 weeks old, were injectednicotinamide (230 mg/kg) intraperitoneally. Fifteen minutes afterinjection, they were injected streptozotocin (85 mg/kg) intravenouslyfrom tail vain under anesthesia with ether. After a week, rats werefasted overnight and then glucose tolerance test (2 g/kg) was done. Therats which showed plasma glucose concentration at 1 hour after glucoseload was over 300 mg/dL were selected to use liquid meal tolerance test.

2) Liquid Meal Tolerance Test

After overnight fasted, the diabetic rats were orally administered atest compound (1 mg/kg), which was dissolved in distilled water, in thedrug-treating group, or distilled water alone in a control group.Immediately after the compound administration, 17.25 kcal/kg of liquidmeal (No. 038, Control diet, assorted with dextrin and maltose; OrientalYeast Co., Ltd.) was loaded orally. The blood was collected from tailartery immediately before and after administration with the time course,and treated with heparin immediately. The blood was centrifuged, and theplasma was collected to quantify the plasma glucose concentration byglucose oxidase method. Plasma glucose concentrations at pretreatment(Oh), 0.5 and 1 hour after the drug administration are shown in Table 2.The values in the table are presented as the mean ±S.E.

TABLE 2 Test Plasma glucose concentration (mg/dL) compound 0 h 0.5 h 1 hControl 117 ± 8 326 ± 46 297 ± 35 Example 21 118 ± 9 156 ± 15 178 ± 19Control 121 ± 7 313 ± 33 303 ± 63 Example 30 121 ± 6 163 ± 8  187 ± 9 Control  140 ± 11 280 ± 22 287 ± 23 Example 32 125 ± 8 223 ± 20 278 ± 32Example 33  127 ± 11 207 ± 8  251 ± 21 Control  116 ± 11 241 ± 15 237 ±10 Example 48 112 ± 5 139 ± 4  132 ± 4  Control 133 ± 9 236 ± 9  210 ±11 Example 57 126 ± 6 149 ± 7  158 ± 10 Control 122 ± 6 277 ± 16 272 ±21 Example 61 116 ± 6 136 ± 6  172 ± 37

Test Example 3 Acute Toxicity Test

Male ICR mice (CLEA Japan, Inc.; 32-37 g, n=5), aged 6 weeks old, werefasted for 4 hours. A test compound, which was dissolved in distilledwater, was administered orally at a dose of 1 g/kg, and then mice wereobserved for 24 hours. The results are shown in the following Table 3.

TABLE 3 Test compound Number of death Example 57 0/5

INDUSTRIAL APPLICABILITY

The pyrazole derivatives represented by the above general formula (I) ofthe present invention, pharmaceutically acceptable salts thereof andprodrugs thereof exert an inhibitory activity inhuman SGLT1 and cansuppress increase of blood glucose level by inhibiting absorption ofcarbohydrate such as glucose at the small intestine, and particularly,can normalize postprandial hyperglycemia by delaying carbohydrateabsorption based on the mechanism. Therefore, the present invention canprovide excellent agents for the prevention or treatment of a diseaseassociated with hyperglycemia such as diabetes, impaired glucosetolerance, diabetic complications, obesity or the like. In addition,since the pyrazole derivatives represented by the above general formula(II) of the present invention and salts thereof are important asintermediates in the production of the pyrazole derivatives representedby the above general formula (I), the compounds represented by the abovegeneral formula (I) of the present invention can be readily prepared viasuch compounds.

1. A pharmaceutical combination which comprises (A) a pyrazolederivative represented by the general formula:

wherein R¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkyl group, aC₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl group, an aryl group which mayhave the same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, or an aryl(C₁₋₆ alkyl) group whichmay have the same or different 1 to 3 substituents selected from thegroup consisting of a halogen atom, a hydroxy group, an amino group, aC₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring; one of Q and Trepresents a group represented by the formula:

or a group represented by the formula:

while the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group,a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group;R² represents a hydrogen atom, a halogen atom, a hydroxy group, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a halo(C₁₋₆alkyl) group, a halo(C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-substituted (C₁₋₆alkoxy) group, a C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group or agroup of the general formula: -A-R⁸ in which A represents a single bond,an oxygen atom, a methylene group, an ethylene group, —OCH₂— or —CH₂O—;and R⁸ represents a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkylgroup, an aryl group which may have the same or different 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, an amino group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,a C₂₋₆ alkenyloxy group, a halo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl)group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, a cyano group and anitro group, or a heteroaryl group which may have a substituent selectedfrom the group consisting of a halogen atom and a C₁₋₆ alkyl group; Xrepresents a single bond, an oxygen atom or a sulfur atom; Y representsa single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group with theproviso that X is a single bond when Y is a single bond; Z represents acarbonyl group or a sulfonyl group; R⁴ and R⁵ are the same or different,and each represents a hydrogen atom or a C₁₋₆ alkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (i), or they bind together with the neighboringnitrogen atom to form a C₂₋₆ cyclic amino group which may have asubstituent selected from the group consisting of a C₁₋₆ alkyl group anda hydroxy(C₁₋₆ alkyl) group; R³, R⁶ and R⁷ are the same or different,and each represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl groupor a C₁₋₆ alkoxy group; and substituent group (i) consists of a hydroxygroup, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono ordi[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a sulfamide group,a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamidegroup, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a groupof the general formula: —CON(R⁹)R¹⁰ in which R⁹ and R¹⁰ are the same ordifferent, and each represents a hydrogen atom or a C₁₋₆ alkyl groupwhich may have the same or different 1 to 3 substituents selected fromthe group consisting of a hydroxy group, an amino group, a mono ordi(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group,an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylaminogroup, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or theybind together with the neighboring nitrogen atom to form a C₂₋₆ cyclicamino group which may have a substituent selected from the groupconsisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, a C₃₋₇cycloalkyl group a C₂₋₆ heterocycloalkyl group, an aryl group which mayhave the same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have asubstituent selected from the group consisting of a halogen atom and aC₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituentselected from the group consisting of a C₁₋₆ alkyl group and ahydroxy(C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group whichmay have a C₁₋₆ alkyl group as a substituent, a pharmaceuticallyacceptable salt thereof or a prodrug thereof, and (B) at least onemember selected from the group consisting of an insulin sensitivityenhancer, a glucose absorption inhibitor, a biguanide, an insulinsecretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, aglucagon receptor antagonist, an insulin receptor kinase stimulant, atripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor,a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylaseinhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphataseinhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesisinhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor,glucagon-like peptide-1, a glucagon-like peptide-1 analogue, aglucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylinagonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase 1 C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128,antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor,probcol, a thyroid hormone receptor agonist, acholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.
 2. A method for the treatment of a disease associated withhyperglycemia, which comprises administering an effective amount of (A)a pyrazole derivative represented by the general formula:

wherein R¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkyl group, aC₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group, an aryl group which mayhave the same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, or an aryl(C₁₋₆ alkyl) group whichmay have the same or different 1 to 3 substituents selected from thegroup consisting of a halogen atom, a hydroxy group, an amino group, aC₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring; one of Q and Trepresents a group represented by the formula:

or a group represented by the formula:

while the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group,a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group;R² represents a hydrogen atom, a halogen atom, a hydroxy group, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a halo(C₁₋₆alkyl) group, a halo(C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy-substituted (C₁₋₆alkoxy) group, a C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group or agroup of the general formula: -A-R⁸ in which A represents a single bond,an oxygen atom, a methylene group, an ethylene group, —OCH₂— or —CH₂O—;and R⁸ represents a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkylgroup, an aryl group which may have the same or different 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, an amino group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,a C₂₋₆ alkenyloxy group, a halo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl)group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, a cyano group and anitro group, or a heteroaryl group which may have a substituent selectedfrom the group consisting of a halogen atom and a C₁₋₆ alkyl group; Xrepresents a single bond, an oxygen atom or a sulfur atom; Y representsa single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group with theproviso that X is a single bond when Y is a single bond; Z represents acarbonyl group or a sulfonyl group; R⁴ and R⁵ are the same or different,and each represents a hydrogen atom or a C₁₋₆ alkyl group which may havethe same or different 1 to 3 groups selected from the followingsubstituent group (i), or they bind together with the neighboringnitrogen atom to form a C₂₋₆ cyclic amino group which may have asubstituent selected from the group consisting of a C₁₋₆ alkyl group anda hydroxy(C₁₋₆ alkyl) group; R³, R⁶ and R⁷ are the same or different,and each represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl groupor a C₁₋₆ alkoxy group; and substituent group (i) consists of a hydroxygroup, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono ordi[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a sulfamide group,a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamidegroup, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a groupof the general formula: —CON(R⁹)R¹⁰ in which R⁹ and R¹⁰ are the same ordifferent, and each represents a hydrogen atom or a C₁₋₆ alkyl groupwhich may have the same or different 1 to 3 substituents selected fromthe group consisting of a hydroxy group, an amino group, a mono ordi(C₁₋₆ alkylamino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group,an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylaminogroup, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or theybind together with the neighboring nitrogen atom to form a C₂₋₆ cyclicamino group which may have a substituent selected from the groupconsisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, a C₃₋₇cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which mayhave the same or different 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have asubstituent selected from the group consisting of a halogen atom and aC₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituentselected from the group consisting of a C₁₋₆ alkyl group and ahydroxy(C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group whichmay have a C₁₋₆ alkyl group as a substituent, a pharmaceuticallyacceptable salt thereof or a prodrug thereof, and (B) at least onemember selected from the group consisting of an insulin sensitivityenhancer, a glucose absorption inhibitor, a biguanide, an insulinsecretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, aglucagon receptor antagonist, an insulin receptor kinase stimulant, atripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor,a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylaseinhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphataseinhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesisinhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor,glucagon-like peptide-1, a glucagon-like peptide-1 analogue, aglucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylinagonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet-derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761,bimoclomol, sulodexide, Y-128,antidiarrhoics, cathartics, ahydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acidderivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterolacyltransferase inhibitor, probcol, a thyroid hormone receptor agonist,a cholesterol absorption inhibitor, a lipase inhibitor, a microsomaltriglyceride transfer protein inhibitor, a lipoxygenase inhibitor, acarnitine palmitoyl-transferase inhibitor, a squalene synthaseinhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acidderivative, a bile acid sequestrant, a sodium/bile acid cotransporterinhibitor, a cholesterol ester transfer protein inhibitor, an appetitesuppressant, an angiotensin-converting enzyme inhibitor, a neutralendopeptidase inhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.